WO2013063004A1 - Device and method for sustained release of therapeutic agent - Google Patents

Device and method for sustained release of therapeutic agent Download PDF

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Publication number
WO2013063004A1
WO2013063004A1 PCT/US2012/061536 US2012061536W WO2013063004A1 WO 2013063004 A1 WO2013063004 A1 WO 2013063004A1 US 2012061536 W US2012061536 W US 2012061536W WO 2013063004 A1 WO2013063004 A1 WO 2013063004A1
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WO
WIPO (PCT)
Prior art keywords
hydrochloride
therapeutic agent
sodium
delivery device
reservoir
Prior art date
Application number
PCT/US2012/061536
Other languages
French (fr)
Inventor
Alessandro Grattoni
Enrica DE ROSA
Randy Goodall
Lee Hudson
Michael Crowley
Original Assignee
The Board Of Regents Of The University Of Texas System
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Board Of Regents Of The University Of Texas System filed Critical The Board Of Regents Of The University Of Texas System
Priority to CN201280052489.6A priority Critical patent/CN104203220A/en
Priority to CA2853347A priority patent/CA2853347A1/en
Priority to EP12843467.7A priority patent/EP2770984A4/en
Publication of WO2013063004A1 publication Critical patent/WO2013063004A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/14244Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14276Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body specially adapted for implantation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/168Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
    • A61M5/16804Flow controllers
    • A61M5/16827Flow controllers controlling delivery of multiple fluids, e.g. sequencing, mixing or via separate flow-paths
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system

Definitions

  • Therapeutic agent e.g. drug
  • delivery is an important aspect of medical treatment since the efficacy of a drug is directly related to its administration.
  • Some therapies require repetitive drug administration to the patient over a long period of time. In many cases, a long term consistent administration of drug is desirable. In addition, compliance of patients can also be an issue in some cases.
  • therapeutic agent delivery devices that are capable of delivering therapeutic agents in controlled ways is still a challenge.
  • One of the major requirements for an implantable drug delivery device is controlled release of therapeutic agents, ranging from small drug molecules to larger biological molecules. It is particularly desirable to achieve a continuous drug release profile whereby the concentration of drug in the bloodstream remains substantially constant throughout an extended delivery period. It is also desirable to for the implantable drug delivery device to provide the continuous drug release profile via passive control mechanisms to minimize device complexity.
  • solubility of the therapeutic agent can provide dosing and application challenges.
  • a lower solubility of the therapeutic agent can require a greater volume of the therapeutic agent in the implantable delivery device in order to provide an effective dosing level for an extended duration.
  • the volume of the therapeuctic agent, and therefore the implantable delivery device may be prohibitively large. It is therefore desirable to provide for long term dosing of low solubility therapeutic agents in an implantable delivery device with a volume sufficiently small enough to allow for implantation.
  • implantable drug delivery devices may incorporate geometric constraints to provide for a controlled release rate of the therapeutic agent.
  • certain implantable drug delivery devices may utilize nanochannels to restrict the rate at which therapeutic molecules can diffuse from the device.
  • geometric constraints can control the diffusion rate so that it is substantially independent of the concentration of the remaining therapeutic agent within the delivery device.
  • These geometric constraints include nanochannels that are fabricated 2-5 times higher than the hydrodynamic size of the molecules of the agent.
  • the therapeutic molecule is sufficiently small, it can be difficult, if not impossible, to create a geometric constraint dimensioned to provide for a controlled release rate at a thereapeutically-effective level.
  • such small geometric constraints may lead to insufficient release of the agent.
  • Exemplary embodiments of the present disclosure comprise an implantable delivery device comprising a reservoir, a channeled member in fluid communication with the reservoir; and a solid matter therapeutic agent disposed within the reservoir and in fluid communication with the channeled member.
  • a solid matter therapeutic agent within the reservoir can address several issues noted in existing systems.
  • the solid matter therapeutic agent dissolving over time can provide for a more steady concentration of therapeutic agent in the delivery device reservoir.
  • the geometry of the delivery device can be optimized. For example, it may be possible to increase the size of the channels because the concentration of the reservoir is maintained at a more steady level because less geometric constraint is required.
  • a solid matter therapeutic agent may also make it possible to administer therapeutic agents with molecules that would otherwise be difficult to administer consistently at therapeutic levels with a variable-concentration reservoir and a channeled member.
  • the channeled member comprises nanochannels and/or microchannels.
  • the solid matter therapeutic agent may comprise a gel, a paste, and/or an initially dry solid.
  • the dry solid comprises distinct crystals or particles, e.g. powdered or granulated material, while in other
  • the dry solid may be formed as a tablet or other compressed or extruded form.
  • the solid matter comprises a polymer matrix in which the therapeutic agent is intermixed.
  • the therapeutic agent delivery device comprises an injection port configured to receive an injection of the solid matter therapeutic agent, possibly followed by or preceded by an injection of a solvent for the solid matter therapeutic agent.
  • the solvent may also be supplied from body fluids around the implanted device entering through the channels after implantation.
  • Particular embodiments comprise a method of administering a therapeutic agent, where the method comprises inserting an implantable delivery device into an area of a human anatomy, and where the implantable delivery device comprises: a reservoir; a channeled member in fluid communication with the reservoir; and a solid matter therapeutic agent disposed within the reservoir.
  • the method may comprise releasing a portion of the therapeutic agent from the implantable delivery device into the area of the human anatomy.
  • the implantable delivery device is configured to release the therapeutic agent at a substantially constant release rate for a dosage period of at least one week, or at least one month, or at least six months or at least one year.
  • the reservoir comprises a solvent configured to partially dissolve the solid matter therapeutic agent.
  • the reservoir comprises a saturated or supersaturated solution of the therapeutic agent.
  • the implantable delivery device comprises a filter.
  • the filter is disposed between the solid matter therapeutic agent and the channeled member.
  • the filter comprises microchannels and or nanochannels.
  • the channeled member comprises microchannels and or nanochannels.
  • Coupled is defined as connected, although not necessarily directly, and not necessarily mechanically.
  • a step of a method or an element of a device that "comprises,” “has,” “includes” or “contains” one or more features, possesses those one or more features, but is not limited to possessing only those one or more features.
  • a device or structure that is configured in a certain way is configured in at least that way, but may also be configured in ways that are not listed.
  • channeled member includes structures comprising microchannels and/or nanochannels, including not limited to, any of the exemplary nanochannel devices disclosed in U.S. Patent Application Serial No. 12/618,233 filed November 13, 2009 (U.S. Patent Publication 20100152699) and entitled “Nanochanneled Device and Related Methods” and International Patent Application Number
  • microchannel is defined as a channel with a cross-section having at least one dimension (e.g. height, width, diameter, etc.) that is greater than 200 nm and less than 50 ⁇ .
  • nanochannel is defined as a channel with a cross-section having at least one dimension (e.g. height, width, diameter, etc.) that is less than 500 nm.
  • FIG. 1 is a graph that illustrates a plasma drug concentration over time when the drug is administered via traditional intravenous (IV) methods.
  • FIG. 2 is a graph that illustrates a plasma drug concentration over time when the drug is administered via a solid matter therapeutic agent in an implantable delivery device.
  • FIG. 3 is a perspective view of an implantable delivery device.
  • FIG. 4 is a section view of the embodiment of FIG. 3.
  • FIG. 5 is a section view of the embodiment of FIG. 3 with a solid matter therapeutic agent inserted into the implantable delivery device.
  • FIG. 6 is a section view of the embodiment of FIG. 3 with a solid matter therapeutic agent inserted into the implantable delivery device.
  • FIG. 7 is a section view of the embodiment of FIG. 3 with multiple therapeutic agents inserted into the implantable delivery device and a filter.
  • FIG. 8 is a graph of an experimental result demonstrating that a solid matter API
  • a more consistent drug administration can provide numerous advantages over periodic high dosage administrations that are initially above the therapeutic range and subsequently diminish to below the therapeutic range.
  • a graph illustrates plasma drug concentration versus time in one example of a typical conventional drug administration utilizing period dosage.
  • the drug concentration is initially significantly above the therapeutic range and subsequently reduces to a level below the therapeutic range.
  • another dosage can be administered and the drug concentration again exceeds the therapeutic range before being reduced into the desired therapeutic range.
  • Figure 2 shows the plasma drug concentration (PDC) over time when the drug is administered via a solid matter therapeutic agent in an implantable delivery device, as described in more detail below.
  • PDC plasma drug concentration
  • IDD 100 an implantable delivery device (IDD) 100 is shown in perspective view (FIG. 3) and sectional views (FIGS. 4-7).
  • IDD 100 comprises a reservoir 110 with a channeled member 130.
  • IDD 100 also comprises an injection port 140 and exit ports 150.
  • channeled member 130 may comprise microchannels, and in specific embodiments, channeled member 130 may comprise nanochannels. Channeled member 130 may also comprise both microchannels and nanochannels in certain
  • channeled member 130 may be an integral component of IDD 100, while in other embodiments, channeled member 130 may be a separate component that is coupled to or inserted into IDD 100.
  • channeled member 130 may be equivalent to the nanochannel delivery device (and may be constructed via the associated methods) disclosed within in U.S. Patent Publication 20100152699, incorporated herein by reference. In other embodiments, channeled member 130 may comprise microchannels without nanochannels.
  • reservoir 110 can be filled with a fully dissolved solution of active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • SMTA solid matter therapeutic agent
  • SMTA 200 may be configured as a paste, gel, powder, degradable compressed polymer matrix mixed with the SMTA, or other solid medium configured to provide a dissolved therapeutic agent within reservoir 110.
  • SMTA 200 is configured as a solid disc shape
  • FIG. 6 SMTA is configured as a powder.
  • SMTA 200 can provide a saturated or supersaturated solution in reservoir 110 that creates a substantially constant drug concentration within reservoir 1 10 for the duration of the desired thereapeutic time period. This can also provide a substantially constant concentration gradient across channeled member 130 for an extended time as the channeled member 130 releases the API of SMTA 200. The solubility limit within reservoir 1 10 keeps dissolution of SMTA 200 limited.
  • SMTA 200 may be injected into reservoir 110 via a needle inserted into injection port 140. A syringe may then be used to force SMTA 200 into reservoir 110. Such a configuration may be used when SMTA 200 is configured, for example, as a gel, paste, powder, microgranules, etc.
  • SMTA 200 may be formed as a solid geometic form, and IDD 100 may be constructed around the solid geometric form, rather than SMTA injected into reservoir 1 10.
  • IDD 100 may comprise a cap to allow SMTA 200 to be inserted within reservoir 110.
  • Reservoir 110 may also comprise a solvent 112 configured to dissolve the SMTA 200.
  • Solvent 1 12 and SMTA 200 may be selected so that SMTA 200 dissolves over an extended period of time, e.g. weeks, months, or years, so that the channeled member 130 release rate is substantially constant. This substantially constant release rate over an extended time period can provide for a more consistent dosage level and more effective therapy.
  • the ability to load IDD 100 with a therapeutic agent in solid form can provide for an increased time period for which IDD 100 can provide an effective level of a desired therapeutic agent (e.g., as compared to an implant loaded with a therapeutic agent in liquid form).
  • the therapeutic time period may comprise several months up to several years.
  • the combination of a saturated or supersatured solution (achieved via dissolution of
  • SMTA 200 in reservoir 1 10) and channeled member 130 can provide for a greater effective thereapeutic period than devices which utilize a channeled member in conjunction with a solution that only contains fully-dissolved SMTA 200.
  • the use of SMTA 200 in a saturated or supersatured solution in reservoir 110 can also be used to reduce the volume of reservoir 1 10. This can allow the overall size of IDD 100 to be reduced and loaded with SMTA 200 for very long durations, and allow it to be implanted or inserted into areas of the human anatomy where it might otherwise not have been possible.
  • the reduction in size for a given amount of SMTA 200 can be estimated by:
  • SMTA Volume Total SMTA (g) / SMTA density (g/ml);
  • R Maximum solubility / SMTA Density.
  • the maximum solubility is less than 1 mg/ml, and the SMTA density is greater than 500 mg/ml, so the necessary size of the reservoir can be reduced by over 500 times.
  • IDD 100 may comprise a filter 120 in reservoir 1 10.
  • filter 120 in certain embodiments with saturated or supersaturated conditions, as SMTA 200 dissolves, it may form particulates containing grains or crystals.
  • the incorporation of filter 120 in IDD 100 can restrict particulate matter greater than a specified size from entering a filtered portion 1 15 of reservoir 1 10 in direct fluid communication with channeled member 130.
  • filter 120 may be a microchanneled or nanochanneled member.
  • filter 120 may be utilized to separate multiple thereapeutic components within IDD 100.
  • IDD 100 comprises a therapeutic component 205 in addition to SMTA 200.
  • certain embodiments may comprise filter 120 without multiple therapeutic components.
  • filter 120 may be used to initially keep SMTA 200 separated from therapeutic component 205.
  • SMTA 200 can dissolve and pass through filter 120 into filtered portion 1 15 before mixing with therapeutic component 205 and passing through channeled member 130 prior to exiting IDD 100.
  • SMTA 200 may comprise stabilizing agents configured to provide a stabilizing effect on therapeutic component 205 in reservoir 1 15.
  • therapeutic component 205 may comprise a fully-solubilized therapeutic agent (e.g. , a complex protein) that may need particular environmental conditions to remain stable over the duration of the release, which could be many months.
  • stabilizing agents of SMTA 200 may comprise molecular stabilizers (e.g., mannitol), solubilizers and surfactants (e.g., sodium laurel sulfate) or other agents that can modulate the molarity, molality, tonicity, or other attributes of filtered portion 115 of reservoir 110.
  • molecular stabilizers e.g., mannitol
  • solubilizers and surfactants e.g., sodium laurel sulfate
  • the dissolution characteristics of the SMTA 200 can control the release of SMTA 200 into the filtered portion 1 15 such that the continuous released amount of the therapeutic component 205 is appropriate to the stabilization needed.
  • SMTA 200 can be configured as a dissolving agent for therapeutic component 205.
  • SMTA 200 may dissolve and pass through filter 120 to reach therapeutic component 205 in filtered portion 115.
  • the interaction of SMTA 200 and therapeutic component 205 can increase the rate therapeutic component 205 dissolves and passes through channeled member 130 before being released from IDD 100.
  • filter 120 can be configured such that it allows molecules of SMTA 200 to pass into filtered portion 115 towards therapeutic component 205, but does not allow molecules of therapeutic component 205 to pass from filtered portion 115 towards SMTA 200.
  • SMTA 200 may be configured to have any number of functions in relation to therapeutic component 205. It is understood that the stabilizing and dissolving functions described above are merely exemplary and that other functions of SMTA 200 may be incorporated in other embodiments.
  • the incorporation of a separation device (e.g., filter 120) and multiple therapeutic components (e.g., SMTA 200 and therapeutic component 205) within an implantable device can eliminate the need to chemically intermix, conjugate, or compound the two molecule types in a single reservoir.
  • SMTA 200 can also provide for more effective dosing of low solubility therapeutic agents, including for example anesthetics.
  • the incorporation of SMTA 200 in IDD 100 can provide for effective dosing of small molecule therapeutic agents that may be difficult to control in liquid form via only a microchanneled or nanochanneled device.
  • IDD 100 can be used to administer a therapeutic agent by loading SMTA 200 into reservoir 110 and inserting IDD 100 into an area of a human anatomy, including for example, subcutaneously. With IDD 100 inserted into the desired anatomical area, SMTA 200 can dissolve over time and release a portion of the therapeutic agent from IDD 100 into the area of the human anatomy or for systemic circulation.
  • SMTA 200 may dissolve or erode by releasing large macroscopic or microscopic particles from its surface. Without restrictions between SMTA 200 and the surrounding environment (e.g., the patient's tissue and circulatory system), such releases could lead to momentary dosage spikes and a release rate of API that is not well regulated.
  • channeled member 130 can restrict such particles from being released from IDD 100 and entering the patient's anatomy.
  • channeled member 130 may comprises channels that are configured to restrict particles of SMTA 200 from being released until they are nearly molecular in size. Such configurations can provide for more constant and predictable releases of API from SMTA 200.
  • IDD 100 may be subjected to various inertial or thermal transients.
  • IDD inertial or thermal transients
  • the movement of the patient's limb can subject IDD 100 to dynamic loading and cause inertial transients of the contents of reservoir 110.
  • IDD 100 Without suitable restriction between an API in a therapeutic implant and the outside environment, such transients could disrupt the established concentration gradients within an implant. In certain cases, this could lead to intermixing between contents of the therapeutic implant and the outside environment.
  • channeled member 130 reduces or eliminates the effects of short term inertial and thermal transients to ensure more stable delivery of API from SMTA 200.
  • channeled member 130 may comprise hundreds of thousands of micro/nano-channels to minimize the effects of such short term inertial and thermal transients.
  • IDD 100 with SMTA 200 can be used to administer therapeutic agents for any number of conditions, including for example delivery of ketoprofen, a non-steroidal antiinflammatory drug with a molecular weight of 254 Daltons and a measured maximum solubility at 25C of 2.5 mg/ml in phosphate buffered saline with 0.01% benzalkonium chloride (PBS/BAK).
  • FIG. 8 illustrates the release of ketoprofen by a nanochanneled member in two cases. In wells 1, 2, and 3, the ketoprofen was fully dissolved at 1.6 mg/ml.
  • thereapeutic agent may comprise one or more of the following substances: adrenergic agent; adrenocortical steroid; adrenocortical suppressant; aldosterone; alkylating agent; antagonist; amino acid; anabolic; analeptic; analgesic;
  • anesthetic anorexogenic; anti-acne agent; anti-adrenergic; anti-allergic; anti-alopecia agent; anti-amebic; anti-anemic; anti-anginal; antiangiogenic, anti-anxiety; anti-arthritic; antiasthmatic; anti-atherosclerotic; antibacterial; antibiotic; anticancer; anticholinergic;
  • anticoagulant ; anticonvulsant; antidepressant; antidiabetic; antidiarrheal; antidiuretic; anti- dyskinetic; anti-emetic; anti-epileptic; antifibrinolytic; antifungal; anti-hemorrhagic;
  • antihistamine anti-hypercalcemic, anti-hypercholesterolaemic; anti-hyperlipidaemic; antihypertensive; anti-hypertriglyceridemic; anti-hypotensive; anti-infective; anti-inflammatory; anti-ischemic; antimicrobial; antimigraine; antimitotic; antimycotic; anti-nauseant; antineoplastic; anti-neutropenic; anti-obesity agent; anti-osteoporotic, antiparasitic;
  • antiproliferative antipsychotic; antiretroviral; anti-res orptives; anti-rheumatic; anti- seborrheic; antisecretory; antispasmodic; antisclerotic; antithrombotic; antitumor; anti- ulcerative; antiviral; appetite suppressant; bisphosphonate; blood glucose regulator; bronchodilator; cardiovascular agent; central nervous system agent; contraceptive;
  • cholinergic cholinergic
  • concentration aid depressant; diagnostic aid; diuretic; DNA-containing agent, dopaminergic agent; estrogen receptor agonist; fertility agent; fibrinolytic; fluorescent agent; free oxygen radical scavenger; gastric acid supressant; gastrointestinal motility effector; glucocorticoid; glutamatergic agent; hair growth stimulant; hemostatic; histamine H2 receptor antagonist; hormone; hypocholesterolemic; hypoglycemic; hypolipidemic;
  • hypotensive imaging agent; immunizing agent; immunomodulator; immunostimulant;
  • immunosuppressant interleukin, keratolytic; LHRH agonist; mood regulator; mucolytic; mydriatic; nasal decongestant; neuromuscular blocking agent; neuroprotective; NMDA antagonist; non- hormonal sterol derivative; nootropic agent; parasympathomimetic agent; plasminogen activator; platelet activating factor antagonist; platelet aggregation inhibitor; platinum-containing agent, psychotropic; radioactive agent; raf antagonist, RNA-containing agent, scabicide; sclerosing agent; sedative; sedative-hypnotic; selective adenosine Al antagonist; selective estrogen receptor modulator, serotonin antagonist; serotonin inhibitor; serotonin receptor antagonist; steroid; stimulant; thrombic agent; thyroid hormone; thyroid inhibitor; thyromimetic; tranquilizer; vasoconstrictor; vasodilator; wound healing agent; xanthine oxidase inhibitor; and the like; Abacavir, Abac
  • Bimatoprost Bisoprolol, Bisoprolol fumarate, Bosentan, Botulin toxin, Budesonide,
  • Metoprolol Metoprolol tartrate, metronidazole, Metronidazole, miglitol, Minocycline,
  • Minocycline hydrochloride mirtazepine, Modafinil, Mometasone, montelukast, Montelukast sodium, Morphine, Moxifloxacin, Mycophenolate mofetil, Naloxone, Naproxen sodium, natalizumab, Neostigmine bromide, Niacin, Nicotinamide, Nifedipine, Nifurtimox, nilotinib hydrochloride monohydrate, nitrofurantoin, Nortriptyline hydrochloride, nystatin, olanzapine, Olanzepine, Olmesartan, olmesartan medoxomil, olopatadine hydrochloride, Omalizumab, Omega-3 acid ethyl esters, Omeprazole, Ondansetron, Orlistat, Oseltamivir, Oxaliplatin, Oxcarbazepine, Oxybytynin chloride, oxycodone hydroch
  • Promethazine Promethazine hydrochloride, Proponolol hydrochloride, Propoxyphene hydrochloride, pseudoephedrine, Pseudophedrine hydrochloride, Pyridostigmine bromide, Pyridoxine hydrochloride, Quetiapine, quetiapine fumarate, Quinapril hydrochloride, Rabeprazole, raloxifene, raltegravir, Ramipril, Ranitidine, Ranitidine hydrochloride,
  • Hydrochloride amelometasone, Ameltolide, Amesergide, Ametantrone Acetate, amezinium metilsulfate, amfebutamone, Amfenac Sodium, Amfiutizole, Amicycline, Amidephrine Mesylate, amidox, Amifloxacin, amifostine, Amilcacin, Amiloride Hydrochloride,
  • Aminocaproic Acid Aminoglutethimide, Aminohippurate Sodium, aminolevulinic acid, Aminophylline, Aminorex, Aminosalicylate sodium, Aminosalicylic acid, Amiodarone, Amiprilose Hydrochloride, Amiquinsin Hydrochloride, amisulpride, Amitraz, Amitriptyline Hydrochloride, Amlexanox, amlodipine, amlodipine besylate, Amobarbital Sodium, Amodiaquine, Amodiaquine Hydrochloride, Amorolfine, Amoxapine, Amoxicillin,
  • oligonucleotides apadoline, apafant, Apalcillin Sodium, apaxifylline, Apazone, aphidicolin glycinate, Apixifylline, Apomorphine Hydrochloride, apraclonidine, Apraclonidine
  • Azanidazole Azaperone, Azaribine, Azaserine, azasetron, Azatadine Maleate, Azathioprine, Azathioprine Sodium, azatoxin, azatyrosine, azelaic acid, Azelastine, azelnidipine,
  • Azepindole Azetepa, azimilide, Azithromycin, Azlocillin, Azolimine, Azosemide,
  • carboxamide-amino-triazo-le carboxyamidotriazole, carboxymethylated beta-l,3-glucan, arV p TM i w- i ⁇ ochloride, CaRest M3, Carfentanil Citrate, Carisoprodol, Carmantadine, Carmustine, CAR 700, Carnidazole, Caroxazone, carperitide, Carphenazine Maleate, Carprofen, Carsatrin Succinate, Cartazolate, carteolol, Carteolol Hydrochloride, Carubicin Hydrochloride, carvedilol, carvotroline, Carvotroline Hydrochloride, carzelesin,
  • Caspofungin castanospermine, caurumonam, cebaracetam, cecropin B, Cedefingol, Cefaclor, Cefadroxil, Cefamandole, Cefaparole, Cefatrizine, Cefazaflur Sodium, Cefazolin, cefcapene pivoxil, cefdaloxime pentexil tosilate, Cefdinir, cefditoren pivoxil, Cefepime, cefetamet, Cefetecol, cefixime, cefluprenam, Cefmenoxime Hydrochloride, Cefmetazole, cefminlox, cefodizime, Cefonicid Sodium, Cefoperazone , Cefoperazone Sodium, Ceforanide, cefoselis, Cefotaxime Sodium, Cefotetan, cefotiam, Cefoxitin, cefozopran, cefpimizole, Cefpiramide, ce
  • Hydrochloride Cetrizine hydrochloride, cetrorelix, Cetuximab, Cetylpyridinium Chloride, Chenodiol, Chlophedianol Hydrochloride, Chloral Betaine, Chlorambucil, Chloramphenicol, Chlordantoin, Chlordiazepoxide, Chlorhexidine Gluconate, chlorins, Chlormadinone Acetate, chloroorienticin A, Chloroprocaine Hydrochloride, Chloropropamide, Chloroquine, chloroquinoxaline sulfonamide, Chlorothiazide, Chlorotrianisene, Chloroxine, Chloroxylenol, Chlorphe niramine Maleate, Chlorphenesin Carbamate, Chlorpheniramine maleate,
  • Chlorpromazine Chlorpromazine hydrochloride, Chlorpropamide, Chlorprothixene,
  • Chlortetracycline Bisulfate Chlorthalidone, Chlorzoxazone, Cholestyramine Resin,
  • cyclobenzaprine hydrochloride cyclobut A, cyclobut G, cyclocapron, Cycloguanil Pamoate, Cycloheximide, cyclopentanthraquinones, Cyclopenthiazide, Cyclopentolate Hydrochloride, Cyclophenazine Hydrochloride, Cyclophosphamide, cycloplatam, Cyclopropane,
  • Dimefadane, Dimefline Hydrochloride Dimenhydrinate, Dimercaprol, Dimethadione, Dimethindene Maleate, Dimethisterone, Dimethyl Sulfoxide, dimethylhomospermine, dimethylprostaglandin Al, dimiracetam, Dimoxamine Hydrochloride, Dinoprost,
  • Esorubicin Hydrochloride Esproquin Hydrochloride, Estazolam, Estradiol, Estramustine, Estrazinol Hydrobromide, Estriol, Estrofurate, Estrogen, Estrone, Estropipate, esuprone, Eszopiclone, Etafedrine Hydrochloride, etanercept, Etanidazole, etanterol, Etarotene, Etazolate Hydrochloride, Eterobarb, ethacizin, Ethacrynate Sodium, Ethacrynic Acid, Ethambutol Hydrochloride, Ethamivan, Ethanolamine Oleate, Ethehlorvynol, Ethembutol hydrochloride, Ethinyl estradiol, Ethiodized Oil, Ethionamide, Ethonam Nitrate,
  • Ferumoxides Ferumoxides, ferumoxsil, Fetoxylate Hydrochloride, Fexofenadine, fexofenadine
  • Fleroxacin flesinoxan, Flestolol Sulfate, Fletazepam, flezelastine, flobufen, Floctafenine, Flordipine, Flosequinan, Floxacillin, Floxuridine, fluasterone, Fluazacort, Flubanilate Hydrochloride, Flubendazole, Flucindole, Flucloronide, Fluconazole, Flucytosine,
  • Fludalanine Fludarabine Phosphate, Fludazonium Chloride, Fludeoxyglucose, Fludorex, Fludrocortisone Acetate, Flufenamic Acid, Flufenisal, Flumazenil, Flumequine, Flumeridone, Flumethasone, Flumetramide, Flumezapine, Fluminorex, Flumizole, Flumoxonide,
  • Flunidazole Flunisolide, Flunitrazepam, Flunixin, fluocalcitriol, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone, Fluorescein, fluorodaunorunicin
  • Fluquazone Fluradoline Hydrochloride, Flurandrenolide, Flurazepam Hydrochloride, Flurbiprofen, Fluretofen, Flurocitabine, Flurofamide, Flurogestone Acetate, Flurothyl, Fluroxene, Fluspiperone, Fluspirilene, Fluticasone, Fluticasone Propionate, Flutroline, Fiuvastatin, Fiuvastatin Sodium, Fluzinamide, Folic Acid, Follicle regulatory protein,
  • Hydrochloride Human chorionic gonadotropin, Human growth hormone, Hycanthone, Hydralazine Hydrochloride, Hydralazine Polistirex, Hydrochlorothiazide, Hydrocodone Bitartrate, Hydrocortisone, Hydroflumethiazide, Hydromorphone Hydrochloride,
  • Isomazole Hydrochloride Isomylamine Hydrochloride, Isoniazid, Isopropamide Iodide, Isopropyl Alcohol, isopropyl unoprostone, Isoproterenol Hydrochloride, Isosorbide,
  • Isosorbide Mononitrate Isotiquimide
  • Isotretinoin Isoxepac
  • Isoxicam Isoxsuprine
  • Hydrochloride isradipine, itameline, itasetron, Itazigrel, itopride, Itraconazole, Ivermectin, ixabepilone, jasplakinolide, Jemefloxacin, Jesopitron, Josamycin, kahalalide F, Kalafungin, Kanamycin Sulfate, ketamine, Ketanserin, Ketazocine, Ketazolam, Kethoxal, Ketipramine Fumarate, Ketoconazole, Ketoprofen, Ketorfanol, ketorolac, Ketotifen Fumarate,
  • Lydimycin Lynestrenol, Lypressin, Lysine, lysofylline, lysostaphin, Maduramicin,
  • Mafenide magainin 2 amide, Magnesium Salicylate, Magnesium Sulfate, magnolol, maitansine, Malethamer, mallotoaponin, mallotochromene, Malotilate, malotilate, mangafodipir, manidipine, maniwamycin A, Mannitol, mannostatin A, manumycin E, ma TM, !
  • TM / v r napinastine Maprotiline, maraviroc, marimastat, Marinol, Masoprocol, maspin, massetolide, Maytansine, Mazapertine Succiniate, Mazindol, Mebendazole, Mebeverine Hydrochloride, Mebrofenin, Mebutamate, Mecamylamine Hydrochloride, Mechlorethamine Hydrochloride, meclizine hydrochloride, Meclocycline, Meclofenamate Sodium, Mecloqualone, Meclorisone Dibutyrate, Medazepam Hydrochloride, Medorinone, Medrogestone, Medroxalol, Medroxyprogesterone, Medrysone, Meelizine Hydrochloride, Mefenamic Acid, Mefenidil, Mefenorex Hydrochloride, Mefexamide, Mefloquine
  • Meptazinol Hydrochloride Mequidox, Meralein Sodium, merbarone, Mercaptopurine, Mercufenol Chloride, Merisoprol, Meropenem, Mesalamine, Meseclazone, Mesoridazine, Mesterolone, Mestranol, Mesuprine Hydrochloride, Metalol Hydrochloride, Metaproterenol Polistirex, Metaraminol Bitartrate, Metaxalone, Meteneprost, meterelin, Metformin, Methacholine Chloride, Methacycline, methadone, Methadyl Acetate, Methalthiazide, Methamphetamine Hydrochloride, Methaqualone, Methazolamide, Methdilazine,
  • Methenamine Methenolone Acetate, Methetoin, Methicillin Sodium, Methimazole, methioninase, Methionine, Methisazone, Methixene Hydrochloride, Methocarbamol, Methohexital Sodium, Methopholine, Methotrexate, Methotrimeprazine, methoxatone, methoxy polyethylene glycol-epoetin beta, Methoxyflurane, Methsuximide,
  • Methyclothiazide Methyl Palmoxirate, Methylatropine Nitrate, Methylbenzethonium Chloride, Methyldopa, Methyldopate Hydrochloride, Methylene Blue, Methylergonovine Maleate, methylhistamine, methylinosine monophosphate, Methylphenidate,
  • Methylprednisolone Methyltestosterone, Methynodiol Diacelate, Methysergide,
  • Mianserin Hydrochloride mibefradil, Mibefradil Dihydrochloridc, Mibolerone, michellamine B, Miconazole, microcolin A, Midaflur, Midazolam Hydrochloride, midodrine, mifepristone, Mifobate, miglitol, milacemide, milameline, mildronate, Milenperone, Milipertine,
  • Mitotane mitoxantrone, mivacurium chloride, mivazerol, mixanpril, Mixidine, mizolastine, mizoribine, Moclobemide, modafinil, Modaline Sulfate, Modecainide, moexipril, mofarotene, Mofegiline Hydrochloride, mofezolac, molgramostim, Molinazone, Molindone
  • Nelezaprine Maleate Nemazoline Hydrochloride
  • nemorubicin Neomycin Palmitate
  • Neostigmine Bromide neridronic acid
  • Netilmicin Sulfate Neutramycin, Nevirapin
  • Pelrinone Hydrochloride Pemedolac, Pemerid Nitrate, Pemetrexed, pemirolast, Pemoline, Penamecillin, Penbutolol Sulfate, Penciclovir, Penfluridol,
  • Penicillamine Penicillin G Benzathine, Penicillin G Potassium, Penicillin G Procaine, Penicillin G Sodium, Penicillin V Hydrabamine, Penicillin V Benzathine, Penicillin V Potassium, Pentabamate, Pentaerythritol Tetranitrate, pentafuside, pentamidine,
  • Pentamorphone Pentamustine, Pentapiperium Methylsulfate, Pentazocine, Pentetic Acid, Pentiapine Maleate, pentigetide, Pentisomicin, Pentizidone Sodium, Pentobarbital,
  • Phenylpropanolamine Hydrochloride Phenylpropanolamine Polistirex, Phenyramidol Hydrochloride, Phenytoin, Phenytoin sodium, Physostigmine, picenadol, picibanil, Picotrin Diolamine, picroliv, picumeterol, pidotimod, Pifarnine, Pilocarpine, pilsicainide, pimagedine, Pimetine Hydrochloride, pimilprost, Pimobendan, Pimozide, Pinacidil, Pinadoline, Pindolol, pinnenol, pinocebrin, Pinoxepin Hydrochloride, pioglitazone, Pipamperone, Pipazethate, pipecuronium bromide, Piperacetazine, Piperacillin, Piperacillin Sodium, Piperamide Maleate, Piperazinc, Pipobroman, Piposulfan, Pi
  • Hydrochloride Prednazate, Prednicarbate, Prednimustine, Prednisolone, prednisolone quetiapine fumerate, Prednisone, Prednival, Pregabalin, Pregnenolone Succiniate, Prenalterol Hydrochloride, Prenylamine, Pridefine Hydrochloride, Prifelone, Prilocaine Hydrochloride, Prilosec, Primaquine Phosphate, Primidolol, Primidone, Prinivil, Prinomide Tromethamine, Prinoxodan, pritosufloxacin, Prizidilol Hydrochloride, Proadifen Hydrochloride, Probenecid, Probicromil Calcium, Probucol, Procainamide Hydrochloride, Procaine Hydrochloride, Procarbazine Hydrochloride, Procaterol Hydrochloride, Prochlorperazine, Procinonide, Pro
  • Proparacaine Hydrochloride Propatyl Nitrate, propentofylline, Propenzolate Hydrochloride, Propikacin, Propiomazine, Propionic Acid, propionylcarnitine, propiram, propiram, propiverine, Propofol, Proponolol hydrochloride, Propoxycaine Hydrochloride,
  • Propoxyphene Hydrochloride Propranolol Hydrochloride, Propulsid, propylbis-acridone, Propylhexedrine, Propyliodone, Propylthiouracil, Proquazone, Prorenoate Potassium, Proroxan Hydrochloride, Proscillaridin, Prostalene, prostratin, Protamine Sulfate, protegrin, Protirelin, Protriptyline Hydrochloride, Proxazole, Proxazole Citrate, Proxicromil,
  • Quadazocine Mesylate Quazepam, Quazinone, Quazodine, Quazolast, quetiapine, quetiapine fumarate, quiflapon, quinagolide, Quinaldine Blue, quinapril, Quinapril hydrochloride, Quinazosin Hydrochloride, Quinbolone, Quinctolate, Quindecamine Acetate, Quindonium Bromide, Quinelorane Hydrochloride, Quinestrol, Quinfamide, Quingestanol Acetate, Quingestrone, Quinidine Gluconate, Quinielorane Hydrochloride, Quinine Sulfate,
  • Repromicin Reproterol Hydrochloride, Reserpine, resinferatoxin, Resorcinol, rrissamulin, retelliptine demethylated, reticulon, reviparin sodium, revonone, rhenium etidronate, rhizoxin, RI retinamide, Ribaminol, Ribavirin, Riboprine, ricasetron, Ridogrel, Rifabutin, Rifametane, Rifamexil,.
  • Salicylamide Salicylate Meglumine, Salicylic Acid, Salmeterol, Salnacediin, Salsalate, sameridine, sampatrilat, Sancycline, sanfetrinem, Sanguinarium Chloride, Saperconazole, saprisartan, sapropterin, sapropterin dihydrochloride, saquinavir, Sarafloxacin Hydrochloride, Saralasin Acetate, sarcophytol A, sargramostim, Sarmoxicillin, Sarpicillin, sarpogrelate, saruplase, saterinone, satigrel, satumomab pendetide, Scopafungin, Scopolamine
  • Sulfacytine Sulfadiazine, Sulfadoxine, Sulfalene, Sulfamerazine, Sulfameter,
  • Sulfamethazine Sulfamethizole, Sulfamethoxazole, Sulfamonomethoxine, Sulfamoxole, Sulfanilate Zinc, Sulfanitran, sulfasalazine, Sulfasomizole, Sulfazamet, Sulfinalol
  • Hydrochloride sulfinosine, Sulfinpyrazone, Sulfisoxazole, Sulfomethoxazole, Sulfomyxin, Sulfonterol Hydrochloride, sulfoxamine, Sulinldac, Sulmarin, Sulnidazole, Suloctidil, Sulofenur, sulopenem, Suloxifen Oxalate, Sulpiride, Sulprostone, sultamicillin, Sulthiame, sultopride, sulukast, Sumarotene, sumatriptan, Sumatriptan succinate, Suncillin Sodium, Suproclone, Suprofen, suradista, suramin, Surfomer, Suricainide Maleate, Suritozole, Suronacrine Maleate, Suxemerid Sulfate, swainsonine, symakalim, Symclosene, Symetine Hydrochlor
  • Tetracaine Tetracaine
  • tetrachlorodecaoxide Tetracycline
  • Tetracycline hydrochloride Tetrahydrozoline Hydrochloride
  • Tetramisole Hydrochloride Tetrazolast Meglumine
  • tetrazomine Tetrafluoride
  • Tetrofosmin Tetroquinone
  • Tetroxoprim Tetrydamine
  • thaliblastine Tetrydamine
  • Tonazocine Mesylate Topiramate, topotecan, Topotecan Hydrochloride, topsentin,
  • Topterone Toquizine, torasemide, toremifene, Torsemide, Tosifen, Tosufloxacin, totipotent stem cell factor (TSCF), Tracazolate, trafermin, Tralonide, Tramadol, Tramadol
  • Trihexyphenidyl Hydrochloride Trilostane, Trimazosin Hydrochloride, trimegestone, Trimeprazine Tartrate, Trimethadione, Trimethaphan Camsylate, Trimethoprim, Trimetozine, Trimetrexate, Trimipramine, Trimoprostil, Trimoxamine Hydrochloride, Triolein, Trioxifene Mesylate, Tripamide, Tripelennamine Hydrochloride, Triprolidine Hydrochloride,
  • Troleandomycin trombodipine, trometamol, Tropanserin Hydrochloride, Tropicamide, tropine, tropisetron, trospectomycin, trovafloxacin, trovirdine, Tryptophan, Tuberculin, Tubocurarine Chloride, Tubulozole Hydrochloride, tucarcsol, tulobuterol, turosteride, Tybamate, tylogenin, Tyropanoate Sodium, Tyrosine, Tyrothricin, tyrphostins, ubenimex,

Abstract

Devices and methods for administering a therapeutic agent, comprising an implantable delivery device. Exemplary embodiments comprise a reservoir in fluid communication with a channeled member, and a solid matter therapeutic agent disposed within the reservoir.

Description

DESCRIPTION
DEVICE AND METHOD FOR SUSTAINED RELEASE OF THERAPEUTIC AGENT BACKGROUND INFORMATION
This application claims benefit of priority to U.S. Provisional Application Serial No. 61/550,774, filed October 24, 201 1, the entire contents of which are hereby incorporated by reference.
Therapeutic agent (e.g. drug) delivery is an important aspect of medical treatment since the efficacy of a drug is directly related to its administration. Some therapies require repetitive drug administration to the patient over a long period of time. In many cases, a long term consistent administration of drug is desirable. In addition, compliance of patients can also be an issue in some cases.
Considerable advances have been made in the field of drug delivery technology over the last three decades, resulting in many breakthroughs in clinical medicine. The creation of therapeutic agent delivery devices that are capable of delivering therapeutic agents in controlled ways is still a challenge. One of the major requirements for an implantable drug delivery device is controlled release of therapeutic agents, ranging from small drug molecules to larger biological molecules. It is particularly desirable to achieve a continuous drug release profile whereby the concentration of drug in the bloodstream remains substantially constant throughout an extended delivery period. It is also desirable to for the implantable drug delivery device to provide the continuous drug release profile via passive control mechanisms to minimize device complexity.
These devices have the potential to improve therapeutic efficacy, diminish potentially life-threatening side effects, improve patient compliance, minimize the intervention of healthcare personnel, reduce the duration of hospital stays, and decrease the diversion of regulated drugs to abusive uses.
By providing a more consistent release it is possible to improve the therapeutic efficacy and simultaneously decrease the side effects (e.g. toxicity of temporary overdosing or diminished activity associated with a small drug concentration in the plasma) associated with multiple injections of higher dosages. In certain instances, solubility of the therapeutic agent can provide dosing and application challenges. For example, a lower solubility of the therapeutic agent can require a greater volume of the therapeutic agent in the implantable delivery device in order to provide an effective dosing level for an extended duration. In cases where it is desirable to have an extended dosing period, the volume of the therapeuctic agent, and therefore the implantable delivery device, may be prohibitively large. It is therefore desirable to provide for long term dosing of low solubility therapeutic agents in an implantable delivery device with a volume sufficiently small enough to allow for implantation.
In certain applications, implantable drug delivery devices may incorporate geometric constraints to provide for a controlled release rate of the therapeutic agent. For example, certain implantable drug delivery devices may utilize nanochannels to restrict the rate at which therapeutic molecules can diffuse from the device. In particular applications, geometric constraints can control the diffusion rate so that it is substantially independent of the concentration of the remaining therapeutic agent within the delivery device. These geometric constraints include nanochannels that are fabricated 2-5 times higher than the hydrodynamic size of the molecules of the agent. However, if the therapeutic molecule is sufficiently small, it can be difficult, if not impossible, to create a geometric constraint dimensioned to provide for a controlled release rate at a thereapeutically-effective level. In addition, such small geometric constraints may lead to insufficient release of the agent. The issues raised above are merely exemplary of the potential shortcomings of existing systems and are not intended to be an exhaustive listing of the issues addressed by embodiments of the present disclosure.
SUMMARY
Exemplary embodiments of the present disclosure comprise an implantable delivery device comprising a reservoir, a channeled member in fluid communication with the reservoir; and a solid matter therapeutic agent disposed within the reservoir and in fluid communication with the channeled member. The inclusion of a solid matter therapeutic agent within the reservoir can address several issues noted in existing systems. For example, the solid matter therapeutic agent dissolving over time can provide for a more steady concentration of therapeutic agent in the delivery device reservoir. By providing a more steady concentration, rather than a concentration that is initially high and subsequently r^rii i^ri Qc mi rrii† be the case for the solid matter outside the constrained reservoir, the geometry of the delivery device can be optimized. For example, it may be possible to increase the size of the channels because the concentration of the reservoir is maintained at a more steady level because less geometric constraint is required.
The use of a solid matter therapeutic agent may also make it possible to administer therapeutic agents with molecules that would otherwise be difficult to administer consistently at therapeutic levels with a variable-concentration reservoir and a channeled member.
In certain embodiments, the channeled member comprises nanochannels and/or microchannels. In particular embodiments, the solid matter therapeutic agent may comprise a gel, a paste, and/or an initially dry solid. In specific embodiments, the dry solid comprises distinct crystals or particles, e.g. powdered or granulated material, while in other
embodiments the dry solid may be formed as a tablet or other compressed or extruded form. In certain embodiments, the solid matter comprises a polymer matrix in which the therapeutic agent is intermixed.
In certain embodiments, the therapeutic agent delivery device comprises an injection port configured to receive an injection of the solid matter therapeutic agent, possibly followed by or preceded by an injection of a solvent for the solid matter therapeutic agent. The solvent may also be supplied from body fluids around the implanted device entering through the channels after implantation.
Particular embodiments comprise a method of administering a therapeutic agent, where the method comprises inserting an implantable delivery device into an area of a human anatomy, and where the implantable delivery device comprises: a reservoir; a channeled member in fluid communication with the reservoir; and a solid matter therapeutic agent disposed within the reservoir. In specific embodiments, the method may comprise releasing a portion of the therapeutic agent from the implantable delivery device into the area of the human anatomy.
In certain embodiments, the implantable delivery device is configured to release the therapeutic agent at a substantially constant release rate for a dosage period of at least one week, or at least one month, or at least six months or at least one year.
In specific embodiments, the reservoir comprises a solvent configured to partially dissolve the solid matter therapeutic agent. In particular embodiments, the reservoir comprises a saturated or supersaturated solution of the therapeutic agent. In certain embodiments, the implantable delivery device comprises a filter. In specific embodiments, the filter is disposed between the solid matter therapeutic agent and the channeled member. In certain embodiments, the filter comprises microchannels and or nanochannels. In certain embodiments, the channeled member comprises microchannels and or nanochannels.
In the following, the term "coupled" is defined as connected, although not necessarily directly, and not necessarily mechanically.
The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more" or "at least one." The term "about" means, in general, the stated value plus or minus 5%. The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or."
The terms "comprise" (and any form of comprise, such as "comprises" and
"comprising"), "have" (and any form of have, such as "has" and "having"), "include" (and any form of include, such as "includes" and "including") and "contain" (and any form of contain, such as "contains" and "containing") are open-ended linking verbs. As a result, a method or device that "comprises," "has," "includes" or "contains" one or more steps or elements, possesses those one or more steps or elements, but is not limited to possessing only those one or more elements. Likewise, a step of a method or an element of a device that "comprises," "has," "includes" or "contains" one or more features, possesses those one or more features, but is not limited to possessing only those one or more features. Furthermore, a device or structure that is configured in a certain way is configured in at least that way, but may also be configured in ways that are not listed.
The term "channeled member" as used herein includes structures comprising microchannels and/or nanochannels, including not limited to, any of the exemplary nanochannel devices disclosed in U.S. Patent Application Serial No. 12/618,233 filed November 13, 2009 (U.S. Patent Publication 20100152699) and entitled "Nanochanneled Device and Related Methods" and International Patent Application Number
PCT/US 10/30937 filed April 13, 2010 and entitled "Nanochanneled Device and Method of Use", both of which are incorporated herein by reference. The term "microchannel" is defined as a channel with a cross-section having at least one dimension (e.g. height, width, diameter, etc.) that is greater than 200 nm and less than 50 μιη.
The term "nanochannel" is defined as a channel with a cross-section having at least one dimension (e.g. height, width, diameter, etc.) that is less than 500 nm.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will be apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a graph that illustrates a plasma drug concentration over time when the drug is administered via traditional intravenous (IV) methods. FIG. 2 is a graph that illustrates a plasma drug concentration over time when the drug is administered via a solid matter therapeutic agent in an implantable delivery device.
FIG. 3 is a perspective view of an implantable delivery device.
FIG. 4 is a section view of the embodiment of FIG. 3.
FIG. 5 is a section view of the embodiment of FIG. 3 with a solid matter therapeutic agent inserted into the implantable delivery device.
FIG. 6 is a section view of the embodiment of FIG. 3 with a solid matter therapeutic agent inserted into the implantable delivery device.
FIG. 7 is a section view of the embodiment of FIG. 3 with multiple therapeutic agents inserted into the implantable delivery device and a filter. FIG. 8 is a graph of an experimental result demonstrating that a solid matter API
(ketoprofen) can sustain a saturated solution that can provide a higher release rate than a solution below the solubility limit. DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
As previously mentioned, a more consistent drug administration can provide numerous advantages over periodic high dosage administrations that are initially above the therapeutic range and subsequently diminish to below the therapeutic range. Referring to FIG. 1, a graph illustrates plasma drug concentration versus time in one example of a typical conventional drug administration utilizing period dosage. As illustrated in FIG. 1, the drug concentration is initially significantly above the therapeutic range and subsequently reduces to a level below the therapeutic range. When the concentration is reduced to a level below the therapeutic range, another dosage can be administered and the drug concentration again exceeds the therapeutic range before being reduced into the desired therapeutic range.
Figure 2 shows the plasma drug concentration (PDC) over time when the drug is administered via a solid matter therapeutic agent in an implantable delivery device, as described in more detail below. The employment of a solid matter therapeutic agent in an implantable delivery device for constant drug release can improve the efficacy of the treatment. In addition it can avoid frequent injections and, in many cases, reduce or solve the issues of patient compliance.
Referring now to FIGS. 3-5, an implantable delivery device (IDD) 100 is shown in perspective view (FIG. 3) and sectional views (FIGS. 4-7). In this embodiment, IDD 100 comprises a reservoir 110 with a channeled member 130. In the exemplary embodiment shown, IDD 100 also comprises an injection port 140 and exit ports 150.
In particular embodiments, channeled member 130 may comprise microchannels, and in specific embodiments, channeled member 130 may comprise nanochannels. Channeled member 130 may also comprise both microchannels and nanochannels in certain
embodiments. In some embodiments, channeled member 130 may be an integral component of IDD 100, while in other embodiments, channeled member 130 may be a separate component that is coupled to or inserted into IDD 100.
In particular embodiments, channeled member 130 may be equivalent to the nanochannel delivery device (and may be constructed via the associated methods) disclosed within in U.S. Patent Publication 20100152699, incorporated herein by reference. In other embodiments, channeled member 130 may comprise microchannels without nanochannels. In exemplary embodiments, reservoir 110 can be filled with a fully dissolved solution of active pharmaceutical ingredient (API). In the section view of FIGS. 5-7, a solid matter therapeutic agent (SMTA) 200 has been inserted into reservoir 110, which may comprise a solvent. In certain embodiments, SMTA 200 may be configured as a paste, gel, powder, degradable compressed polymer matrix mixed with the SMTA, or other solid medium configured to provide a dissolved therapeutic agent within reservoir 110. In FIG. 5, SMTA 200 is configured as a solid disc shape, while in FIG. 6 SMTA is configured as a powder.
For example, SMTA 200 can provide a saturated or supersaturated solution in reservoir 110 that creates a substantially constant drug concentration within reservoir 1 10 for the duration of the desired thereapeutic time period. This can also provide a substantially constant concentration gradient across channeled member 130 for an extended time as the channeled member 130 releases the API of SMTA 200. The solubility limit within reservoir 1 10 keeps dissolution of SMTA 200 limited.
In particular embodiments, SMTA 200 may be injected into reservoir 110 via a needle inserted into injection port 140. A syringe may then be used to force SMTA 200 into reservoir 110. Such a configuration may be used when SMTA 200 is configured, for example, as a gel, paste, powder, microgranules, etc. In other embodiments, SMTA 200 may be formed as a solid geometic form, and IDD 100 may be constructed around the solid geometric form, rather than SMTA injected into reservoir 1 10. In still other embodiments, IDD 100 may comprise a cap to allow SMTA 200 to be inserted within reservoir 110.
Reservoir 110 may also comprise a solvent 112 configured to dissolve the SMTA 200. Solvent 1 12 and SMTA 200 may be selected so that SMTA 200 dissolves over an extended period of time, e.g. weeks, months, or years, so that the channeled member 130 release rate is substantially constant. This substantially constant release rate over an extended time period can provide for a more consistent dosage level and more effective therapy. The ability to load IDD 100 with a therapeutic agent in solid form can provide for an increased time period for which IDD 100 can provide an effective level of a desired therapeutic agent (e.g., as compared to an implant loaded with a therapeutic agent in liquid form). In certain embodiments, the therapeutic time period may comprise several months up to several years. The combination of a saturated or supersatured solution (achieved via dissolution of
SMTA 200 in reservoir 1 10) and channeled member 130 can provide for a greater effective thereapeutic period than devices which utilize a channeled member in conjunction with a solution that only contains fully-dissolved SMTA 200. The use of SMTA 200 in a saturated or supersatured solution in reservoir 110 can also be used to reduce the volume of reservoir 1 10. This can allow the overall size of IDD 100 to be reduced and loaded with SMTA 200 for very long durations, and allow it to be implanted or inserted into areas of the human anatomy where it might otherwise not have been possible. The reduction in size for a given amount of SMTA 200 can be estimated by:
R = (SMTA Volume + Surrounding Liquid Volume) / (Fully Dissolved Liquid
Volume), where: SMTA Volume = Total SMTA (g) / SMTA density (g/ml);
Surrounding Liquid Volume = volume of saturated or supersatured liquid within a reservoir (ml); and
Fully Dissolved Liquid Volume = Total SMTA (g) / Maximum solubility (g/ml)
If the Surrounding Liquid Volume is small, then R ~ Maximum solubility / SMTA Density. For many compounds, including therapeutic agents, the maximum solubility is less than 1 mg/ml, and the SMTA density is greater than 500 mg/ml, so the necessary size of the reservoir can be reduced by over 500 times.
Referring now to FIG. 7, in certain embodiments IDD 100 may comprise a filter 120 in reservoir 1 10. In certain embodiments with saturated or supersaturated conditions, as SMTA 200 dissolves, it may form particulates containing grains or crystals. The incorporation of filter 120 in IDD 100 can restrict particulate matter greater than a specified size from entering a filtered portion 1 15 of reservoir 1 10 in direct fluid communication with channeled member 130. In some cases, filter 120 may be a microchanneled or nanochanneled member. In particular embodiments, filter 120 may be utilized to separate multiple thereapeutic components within IDD 100. For example, in the embodiment shown in FIG. 7, IDD 100 comprises a therapeutic component 205 in addition to SMTA 200. It is understood that certain embodiments may comprise filter 120 without multiple therapeutic components. In exemplary embodiments, filter 120 may be used to initially keep SMTA 200 separated from therapeutic component 205. In particular embodiments, SMTA 200 can dissolve and pass through filter 120 into filtered portion 1 15 before mixing with therapeutic component 205 and passing through channeled member 130 prior to exiting IDD 100. In one specific embodiment, SMTA 200 may comprise stabilizing agents configured to provide a stabilizing effect on therapeutic component 205 in reservoir 1 15. For example, in certain embodiments, therapeutic component 205 may comprise a fully-solubilized therapeutic agent (e.g. , a complex protein) that may need particular environmental conditions to remain stable over the duration of the release, which could be many months. In certain embodiments, stabilizing agents of SMTA 200 may comprise molecular stabilizers (e.g., mannitol), solubilizers and surfactants (e.g., sodium laurel sulfate) or other agents that can modulate the molarity, molality, tonicity, or other attributes of filtered portion 115 of reservoir 110.
In particular embodiments, the dissolution characteristics of the SMTA 200, as well as the configuration of filter 120, can control the release of SMTA 200 into the filtered portion 1 15 such that the continuous released amount of the therapeutic component 205 is appropriate to the stabilization needed.
In still other embodiments, SMTA 200 can be configured as a dissolving agent for therapeutic component 205. In such embodiments, SMTA 200 may dissolve and pass through filter 120 to reach therapeutic component 205 in filtered portion 115. The interaction of SMTA 200 and therapeutic component 205 can increase the rate therapeutic component 205 dissolves and passes through channeled member 130 before being released from IDD 100. In particular embodiments, filter 120 can be configured such that it allows molecules of SMTA 200 to pass into filtered portion 115 towards therapeutic component 205, but does not allow molecules of therapeutic component 205 to pass from filtered portion 115 towards SMTA 200.
In general, SMTA 200 may be configured to have any number of functions in relation to therapeutic component 205. It is understood that the stabilizing and dissolving functions described above are merely exemplary and that other functions of SMTA 200 may be incorporated in other embodiments. The incorporation of a separation device (e.g., filter 120) and multiple therapeutic components (e.g., SMTA 200 and therapeutic component 205) within an implantable device can eliminate the need to chemically intermix, conjugate, or compound the two molecule types in a single reservoir.
The use of SMTA 200 can also provide for more effective dosing of low solubility therapeutic agents, including for example anesthetics. In addition, the incorporation of SMTA 200 in IDD 100 can provide for effective dosing of small molecule therapeutic agents that may be difficult to control in liquid form via only a microchanneled or nanochanneled device.
IDD 100 can be used to administer a therapeutic agent by loading SMTA 200 into reservoir 110 and inserting IDD 100 into an area of a human anatomy, including for example, subcutaneously. With IDD 100 inserted into the desired anatomical area, SMTA 200 can dissolve over time and release a portion of the therapeutic agent from IDD 100 into the area of the human anatomy or for systemic circulation.
In certain embodiments, it is possible that during use SMTA 200 may dissolve or erode by releasing large macroscopic or microscopic particles from its surface. Without restrictions between SMTA 200 and the surrounding environment (e.g., the patient's tissue and circulatory system), such releases could lead to momentary dosage spikes and a release rate of API that is not well regulated. In the exemplary embodiments disclosed herein, channeled member 130 can restrict such particles from being released from IDD 100 and entering the patient's anatomy. In particular embodiments, channeled member 130 may comprises channels that are configured to restrict particles of SMTA 200 from being released until they are nearly molecular in size. Such configurations can provide for more constant and predictable releases of API from SMTA 200.
In certain embodiments, IDD 100 may be subjected to various inertial or thermal transients. For example, if IDD is subcutaneously inserted into a patient's arm or leg, the movement of the patient's limb can subject IDD 100 to dynamic loading and cause inertial transients of the contents of reservoir 110. Without suitable restriction between an API in a therapeutic implant and the outside environment, such transients could disrupt the established concentration gradients within an implant. In certain cases, this could lead to intermixing between contents of the therapeutic implant and the outside environment. In exemplary embodiments of the present disclosure, channeled member 130 reduces or eliminates the effects of short term inertial and thermal transients to ensure more stable delivery of API from SMTA 200. In particular embodiments, channeled member 130 may comprise hundreds of thousands of micro/nano-channels to minimize the effects of such short term inertial and thermal transients.
The use of IDD 100 with SMTA 200 can be used to administer therapeutic agents for any number of conditions, including for example delivery of ketoprofen, a non-steroidal antiinflammatory drug with a molecular weight of 254 Daltons and a measured maximum solubility at 25C of 2.5 mg/ml in phosphate buffered saline with 0.01% benzalkonium chloride (PBS/BAK). FIG. 8, illustrates the release of ketoprofen by a nanochanneled member in two cases. In wells 1, 2, and 3, the ketoprofen was fully dissolved at 1.6 mg/ml. In wells, 4, 5, and 6, a near-saturated solution with concentration of 2.2 mg/ml had approximately 5.5 mg of ketoprofen powder added, exceeding the maximum solubility of ketoprofen in PBS/BAK, so that solid matter remained in the source wells. The amount of ketoprofen released by the nanochannels into the corresponding sink wells (which simulate the subcutaneous body tissue) was measured by high-performance liquid chromatography (HPLC). FIG. 8 shows that the fully dissolved ketoprofen had a constant release rate of about 0.10 mg/day, while the saturated solutions provided higher constant release rates, ranging from 0.13 to 0.26 mg/day.
In particular embodiments, thereapeutic agent may comprise one or more of the following substances: adrenergic agent; adrenocortical steroid; adrenocortical suppressant; aldosterone; alkylating agent; antagonist; amino acid; anabolic; analeptic; analgesic;
anesthetic; anorexogenic; anti-acne agent; anti-adrenergic; anti-allergic; anti-alopecia agent; anti-amebic; anti-anemic; anti-anginal; antiangiogenic, anti-anxiety; anti-arthritic; antiasthmatic; anti-atherosclerotic; antibacterial; antibiotic; anticancer; anticholinergic;
anticoagulant; anticonvulsant; antidepressant; antidiabetic; antidiarrheal; antidiuretic; anti- dyskinetic; anti-emetic; anti-epileptic; antifibrinolytic; antifungal; anti-hemorrhagic;
antihistamine; anti-hypercalcemic, anti-hypercholesterolaemic; anti-hyperlipidaemic; antihypertensive; anti-hypertriglyceridemic; anti-hypotensive; anti-infective; anti-inflammatory; anti-ischemic; antimicrobial; antimigraine; antimitotic; antimycotic; anti-nauseant; antineoplastic; anti-neutropenic; anti-obesity agent; anti-osteoporotic, antiparasitic;
antiproliferative; antipsychotic; antiretroviral; anti-res orptives; anti-rheumatic; anti- seborrheic; antisecretory; antispasmodic; antisclerotic; antithrombotic; antitumor; anti- ulcerative; antiviral; appetite suppressant; bisphosphonate; blood glucose regulator; bronchodilator; cardiovascular agent; central nervous system agent; contraceptive;
cholinergic; concentration aid; depressant; diagnostic aid; diuretic; DNA-containing agent, dopaminergic agent; estrogen receptor agonist; fertility agent; fibrinolytic; fluorescent agent; free oxygen radical scavenger; gastric acid supressant; gastrointestinal motility effector; glucocorticoid; glutamatergic agent; hair growth stimulant; hemostatic; histamine H2 receptor antagonist; hormone; hypocholesterolemic; hypoglycemic; hypolipidemic;
hypotensive; imaging agent; immunizing agent; immunomodulator; immunostimulant;
immunosuppressant; interleukin, keratolytic; LHRH agonist; mood regulator; mucolytic; mydriatic; nasal decongestant; neuromuscular blocking agent; neuroprotective; NMDA antagonist; non- hormonal sterol derivative; nootropic agent; parasympathomimetic agent; plasminogen activator; platelet activating factor antagonist; platelet aggregation inhibitor; platinum-containing agent, psychotropic; radioactive agent; raf antagonist, RNA-containing agent, scabicide; sclerosing agent; sedative; sedative-hypnotic; selective adenosine Al antagonist; selective estrogen receptor modulator, serotonin antagonist; serotonin inhibitor; serotonin receptor antagonist; steroid; stimulant; thrombic agent; thyroid hormone; thyroid inhibitor; thyromimetic; tranquilizer; vasoconstrictor; vasodilator; wound healing agent; xanthine oxidase inhibitor; and the like; Abacavir, Abacavir sulfate, abatacept, Acarbose, Acetaminophen, Aciclovir, Adalimumab, Adapalene, Alendronate, Alendronate sodium, Alfuzosin, aliskiren, allopurinol, alvimopan, ambrisentan, Aminocaproic acid, Amitriptyline hydrochloride, amlodipine, amlodipine besylate, amoxicillin, amoxicilline, Amphetamine, Anastrozole, Aripiprazole, armodafinil, Atazanavir, atenolol, Atomoxetine, atorvastatin calcium, atorvastatin, Atropine sulfate, Azelastine, azithromycin, Balsalazide, Benazepril, bendamustine hydrochloride, Benzepril hydrochloride, bevacizumab, Bicalutamide,
Bimatoprost, Bisoprolol, Bisoprolol fumarate, Bosentan, Botulin toxin, Budesonide,
Buformin, Buprenorphine, Bupropion, bupropion hydrobromide, Bupropion Hydrochloride, Cabergoline, Calcipotriol, calcitriol, candesartan cilexetil, Capecitabine, Captopril, carbidopa, carisoprodol, Carvedilol, Caspofungin, Cefdinir, Cefoperazone , Cefotiam, cefprozil, Cefuroxime, Celecoxib, cephalaxin, Certolizumab Pegol, Cetirizine, Cetrizine hydrochloride, Cetuximab, Chlorpromazine hydrochloride, Chlorpheniramine maleate, ciclesonide,
Cilastatin, cimetidine, Cinacalcet, Ciprofloxacin, citalopram hydrobromide, Clarithromycin, Clindamycin, Clindamycin, clindamycin hydrochloride, Clomipramine hydrochloride, Clonidine hydrochloride, clopidogrel, Clopidogrel bisulfate, Cloxacillin Sodium, Co- Amoxiclav, Codeine phosphate, Colchicines, Colesevelam, cyclobenzaprine hydrochloride, ^ nnhncnh am^Q^ Cyclosporine, darbepoetin alfa, Darifenacin, DCRM 197 protein, Desloratadine, desloratidine, Desmopressin sulfate, Desoximetasone, dexamethasone, Diclofenac, Diethylcarbamazine citrate, difluprednate, diphenhydramine, Dipyridamole, DL- methionine, Docetaxel, Donepezil, doripenem, Dorzolamide, Doxazosin, doxazosin mesylate, doxycydine, Drospirenone, Duloxetine, Dutasteride, eculizumab, Efavirenz, Emtricitabine, Enalapril, enalapril maleate, Enoxaparin Sodium, Eprosartan, Erlotinib, Erythromycin, Erythropoetin, Escitalopram, esomeprazole, estradiol, Estrogen, Eszopiclone, etanercept, Ethembutol hydrochloride, Ethosuximide, ethynl estradiol, etonogestrel, etoricoxib, etravirine, Exenatide, Ezetimibe, Ezetimibe, Factor VII, famotidine, Famotidine, Fenofibrate, Fenofibrate, Fentanyl, Fentanyl citrate, Ferrous sulfate, Fexofenadine, fexofenadine hydrochloride, Filgrastim, Finasteride, fluconazole, Fluoxetine hydrochloride, Fluticasone, Fluvastatin, folic acid, Follitropin alfa, Follitropin beta, Formoterol, Fosinopril sodium, Gabapentin, Gabapentin, Gemcitabine, glargine insulin, Glatiramer, glimepride, Goserelin, histrelin acetate, Human growth hormone, Hydralazine hydrochloride, Hydrocodone bitartrate, Hydroxyurea, Hydroxyzine hydrochloride, Ibandronate, Imatinib, Imiglucerase, Imipenem, imiquimod, Indinavir sulfate, infliximab, Interferon beta- la, Ipratropium,
Irbesartan, Irinotecan, Isoniazid, Isosorbide moninitrate, ixabepilone, ketamine, ketoconazole, Ketorolac, Lactobionate, Lamivudine, Lamivudine, Lamotrigine, lanreotide acetate,
Lansoprazole, lapatinib, laropiprant, Latanoprost, Letrozole, Leuprolide, Levalbuterol, Levamisole hydrochloride, Levetiracetam, levocetirizine dihydrochloride, levodopa,
Levofloxacin, levonorgestrel, Levothyroxine, levothyroxine sodium, Lidocaine, Linezolid, Lisdexamfetamine Dimesylate, Lisinopril, Lispro insulin, Lopinavir, Loratadine, lorazepam, Losartan potassium, maraviroc, Marinol, meclizine hydrochloride, Meloxicam, Memantine, Meropenem, metaxalone, metformin, Metformin Hydrochloride, methadone, methoxy polyethylene glycol-epoetin beta, Methylphenidate, Methylphenidate hydrochloride,
Metoprolol, Metoprolol tartrate, metronidazole, Metronidazole, miglitol, Minocycline,
Minocycline hydrochloride, mirtazepine, Modafinil, Mometasone, montelukast, Montelukast sodium, Morphine, Moxifloxacin, Mycophenolate mofetil, Naloxone, Naproxen sodium, natalizumab, Neostigmine bromide, Niacin, Nicotinamide, Nifedipine, Nifurtimox, nilotinib hydrochloride monohydrate, nitrofurantoin, Nortriptyline hydrochloride, nystatin, olanzapine, Olanzepine, Olmesartan, olmesartan medoxomil, olopatadine hydrochloride, Omalizumab, Omega-3 acid ethyl esters, Omeprazole, Ondansetron, Orlistat, Oseltamivir, Oxaliplatin, Oxcarbazepine, Oxybytynin chloride, oxycodone hydrochloride, Paclitaxel, Palivizumab, Pantoprazole, paracetamol, Paroxetine, paroxetine hydrochloride, Pegylated interferon alfa- q Penicillamine, Penicillin V potassium, Phenformin, Phenytoin sodium, Pioglitazone, Piperacillin, Potassium chloride, Pramipexole, Pravastatin, Pravastatin sodium, prednisolone quetiapine fumerate, Pregabalin, Primaquine phosphate, Progesterone,
Promethazine, Promethazine hydrochloride, Proponolol hydrochloride, Propoxyphene hydrochloride, pseudoephedrine, Pseudophedrine hydrochloride, Pyridostigmine bromide, Pyridoxine hydrochloride, Quetiapine, quetiapine fumarate, Quinapril hydrochloride, Rabeprazole, raloxifene, raltegravir, Ramipril, Ranitidine, Ranitidine hydrochloride,
Recombinant factor VIII, retapamulin, Rimonabant, Risedronate, Risedronate sodium, risperidone, Ritonavir, rituximab, Rivastigmine, rivastigmine tartrate, Rizatriptan, Ropinirole, rosiglitazone, Rosiglitazone maleate, Rosuvastatin, Rotavirus vaccine, rotigotine, Salbutamol, Salbutamol sulfate, salmeterol, sapropterin dihydrochloride, Sertraline, sertraline
hydrochloride, Sevelamer, Sevoflurane, Sildenafil, sildenafil citrate, simvastatin, Simvastatin, Sitagliptin, Sodium valproate, Solifenacin, Somatostatin, Somatropin, Stavudine,
Sulfomethoxazole, Sumatriptan, Sumatriptan succinate, Tacrolimus, Tadalafil, tamoxifen citrate, Tamsulosin, tamsulosin hydrochloride, Tegaserod, Telmisartan, temazepam,
Temozolomide, temsirolimus, Tenofovir, Terazosin Hydrochloride, Terbinafine, Teriparatide, testosterone, Tetracycline hydrochloride, Thalidomide, thymopentin, Timolol meleate, Tiotropium, tipranavir, Tolterodine, tolterodine tartrate, topiramate, topotecan, Tramadol, Tramodol hydrochloride, trastuzumab, trazodone hydrochloride, trimethoprim, Valaciclovir, Valacyclovir hydrochloride, Valproate semisodium, valsartan, Vancomycin, Vardenafil, Varenicline, venlafaxine, Venlafaxine hydrochloride, Verapamil Hydrochloride, vildagliptin, Voglibose, Voriconazole, Wafarin sodium acetylsalicylic acid, Zaleplon, Zidovudine, Ziprasidone, Zoledronate, Zolpidem, or pharmaceutically acceptable salts thereof; 16-alpha fluoroestradiol, 17-alpha dihydroequilenin, 17-alpha estradiol, 17-beta estradiol, 17- hydroxyprogesterone, 1 -dodecpyrrolidinone, 22-oxacalcitriol, 3-isobutyl-gammabutyric acid, 6-fluoroursodeoxycholic acid, 7-methoxytacrine, Abacavir, Abacavir sulfate, Abamectin, abanoquil, abatacept, abecarnil, abiraterone, Ablukast, Ablukast Sodium, Acadesine, acamprosate, Acarbose, Acebutolol, Acecainide Hydrochloride, Aceclidine, aceclofenae, Acedapsone, Acedapsone, Aceglutamide Aluminum, Acemannan, Acetaminophen,
Acetazolamide, Acetohexamide, Acetohydroxamic Acid, acetomepregenol, Acetophenazine Maleate, Acetosulfone Sodium, Acetylcholine Chloride, Acetylcysteine, acetyl-L-carnitine, acetylmethadol, Aciclovir, Acifran, acipimox, acitemate, Acitretin, Acivicin, Aclarubicin, aclatonium, Acodazole Hydrochloride, aconiazide, Acrisorcin, Acrivastine, Acronine, Actisomide, Actodigin, Acyclovir, acylfulvene, Adatanserin Hydrochloride, adafenoxate, A ^ ai i rmimah A dapalene, adatanserin, adecypenol, adecypenol, Adefovir, adelmidrol, ademetionine, Adenosine, Adinazolam, Adipheinine Hydrochloride, adiposin, Adozelesin, adrafinil, Adrenalone, Aiclometasone Dipropionate, airbutamine, alacepril, Alamecin, Alanine, Alaproclate, alaptide, Albendazole, albolabrin, Albuterol, Alclofenae, Alcloxa, aldecalmycin, Aldesleukin, Aldioxa, Aletamine Hydrochloride, Alendronate, Alendronate Sodium, alendronic acid, alentemol, Alentemol Hydrobromide, Aleuronium Chloride, Alexidine, alfacalcidol, Alfentanil Hydrochloride, alfuzosin, Algestone Acetonide, alglucerase, Aliflurane, alinastine, Alipamide, aliskiren, Allantoin, Allobarbital, Allopurinol, Alonimid, alosetron, Alosetron Hydrochloride, Alovudine, Alpertine, alpha-idosone, Alpidem, Alprazolam, Alprenolol Hydrochloride, Alprenoxime Hydrochloride, Alprostadil, Alrestatin Sodium, Altanserin Tartrate, Alteplase, Althiazide, Altretamine, altromycin B, Alverinc Citrate, alvimopan, Alvircept Sudotox, Amadinone Acetate, Amantadine
Hydrochloride, ambamustine, Ambomycin, ambrisentan, Ambruticin, Ambuphylline, Ambuside, Amcinafal, Amcinonide, Amdinocillin, Amdinocillin Pivoxil, Amedalin
Hydrochloride, amelometasone, Ameltolide, Amesergide, Ametantrone Acetate, amezinium metilsulfate, amfebutamone, Amfenac Sodium, Amfiutizole, Amicycline, Amidephrine Mesylate, amidox, Amifloxacin, amifostine, Amilcacin, Amiloride Hydrochloride,
Aminacrine Hydrochloride, Aminobenzoate Potassium, Aminobenzoate Sodium,
Aminocaproic Acid, Aminoglutethimide, Aminohippurate Sodium, aminolevulinic acid, Aminophylline, Aminorex, Aminosalicylate sodium, Aminosalicylic acid, Amiodarone, Amiprilose Hydrochloride, Amiquinsin Hydrochloride, amisulpride, Amitraz, Amitriptyline Hydrochloride, Amlexanox, amlodipine, amlodipine besylate, Amobarbital Sodium, Amodiaquine, Amodiaquine Hydrochloride, Amorolfine, Amoxapine, Amoxicillin,
Amphecloral, Amphetamine, Amphetamine Sulfate, Amphomycin, Amphoterin B,
Ampicillin, ampiroxieam, Ampyzine Sulfate, Amquinate, Amrinone, amrubicin, Amsacrine, Amylase, amylin, amythiamicin, Anagestone Acetate, anagrelide, Anakinra, ananain, anaritide, Anaritide Acetate, Anastrozole, Anazolene Sodium, Ancrod, andrographolide, Androstenedione, Angiotensin Amide, Anidoxime, Anileridine, Anilopam Hydrochloride, Aniracetam, Anirolac, Anisotropine Methylbromide, Anistreplase, Anitrazafen, anordrin, antagonist D, antagonist G, antarelix, Antazoline Phosphate, Anthelmycin, Anthralin, Anthramy ci antiandrogen, antiestrogen, antineoplaston, Antipyrine, antisense
oligonucleotides, apadoline, apafant, Apalcillin Sodium, apaxifylline, Apazone, aphidicolin glycinate, Apixifylline, Apomorphine Hydrochloride, apraclonidine, Apraclonidine
Hydrochloride, Apramycin, Aprindine, Aprindine Hydrochloride, aprosulate sodium,
Figure imgf000016_0001
Maleate, aptiganel, apurinic acid, apurinic acid, aranidipine, Aranotin, Arbaprostil, arbekicin, arbidol, Arbutamine Hydrochloride, Arclofenin, Ardeparin Sodium, argatroban, Arginine, Argipressin Tannate, Arildone, Aripiprazole, armodafinil, arotinolol, Arpinocid, Arteflene, Artilide Fumarate, asimadoline, aspalatone, Asparaginase, Aspartic Acid, Aspartocin, asperfuran, Aspirin, aspoxicillin, Asprelin, Astemizole, Astromicin Sulfate, asulacrine, atamestane, Atazanavir, Atenolol, atevirdine, Atipamezole, Atiprosin Maleate, Atolide, Atomoxetine, atorvastatin, Atorvastatin Calcium, Atosiban, Atovaquone, atpenin B, Atracurium Besylate, atrimustine, atrinositol, Atropine, Atropine sulfate, Auranofin, aureobasidin A, Aurothioglucose, Avilamycin, Avoparcin, Avridine, Axid, axinastatin 1, axinastatin 2, axinastatin 3, Azabon, Azacitidinie, Azaclorzine Hydrochloride, Azaconazole, azadirachtine, Azalanstat Dihydrochloride, Azaloxan Fumarate, Azanator Maleate,
Azanidazole, Azaperone, Azaribine, Azaserine, azasetron, Azatadine Maleate, Azathioprine, Azathioprine Sodium, azatoxin, azatyrosine, azelaic acid, Azelastine, azelnidipine,
Azepindole, Azetepa, azimilide, Azithromycin, Azlocillin, Azolimine, Azosemide,
Azotomycin, Aztreonam, Azumolene Sodium, Bacampicillin Hydrochloride, baccatin III, Bacitracin, Baclofen, bacoside A, bacoside B, bactobolamine, balanol, balazipone, balhimycin, balofloxacin, balsalazide, Bambermycins, bambuterol, Bamethan Sulfate, Bamifylline Hydrochloride, Bamnidazole, baohuoside 1, Barmastine, barnidipine, Basic, Basifungin, Batanopride Hydrochloride, batebulast, Batelapine Maleate, Batimastat, beau vericin, Becanthone Hydrochloride, becaplermin, becliconazole, Beclomethasone
Dipropionate, befloxatone, Beinserazide, Belfosdil, Belladonna, Beloxamide, Bemesetron, Bemitradine, Bemoradan, Benapryzine Hydrochloride, Benazepril, Benazepril
Hydrochloride, Benazeprilat, Benda calol Mesylate, bendamustine hydrochloride, Bendazac, Bendroflumethiazide, benflumetol, benidipine, Benorterone, Benoxaprofen, Benoxaprofen, Benoxinate Hydrochloride, Benperidol, Bentazepam, Bentiromide, Benurestat,
Benzbromarone, Benzepril hydrochloride, Benzethonium Chloride, Benzetimide
Hydrochloride, Benzilonium Bromide, Benzindopyrine Hydrochloride, benzisoxazole, Benzocaine, benzochlorins, Benzoctamine Hydrochloride, Benzodepa, benzoidazoxan, Benzonatate, Benzoyl Peroxide, benzoylstaurosporine, Benzquinamide, Benzthiazide, benztropine, Benztropine Mesylate, Benzydamine Hydrochloride, Benzylpenicilloyl
Polylysine, bepridil, Bepridil Hydrochloride, Beractant, Beraprost, Berefrine, berlafenone, bertosamil, B erythromycin, besipirdine, betaalethine, betaclamycin B, Betamethasone, betamipron, betaxolol, Betaxolol Hydrochloride, Bethanechol Chloride, Bethanidine Sulfate, betulinic acid, bevacizumab, bevantolol, Bevantolol Hydrochloride, Bezafibrate, Bialamicol M ArrsM rs Ao Biapenem, Bicalutamide, Bicifadine Hydrochloride, Biclodil Hydrochloride, Bidisomide, bifemelane, Bifonazole, bimakalim, Bimatoprost, bimithil, Bindarit,
Biniramycin, binospirone, bioxalomycin, Bipenamol Hydrochloride, Biperiden, Biphenamine Hydrochloride, biriperone, bisantrene, bisaramil, bisaziridinylspermine, bis-benzimid zole A, bis-benzimidazole B, bisnafide, Bisobrin Lactate, Bisoprolol, Bisoprolol fumarate,
Bispyrithione Magsulfex, bistramide D, bistramide K, bistratene A, Bithionolate Sodium, Bitolterol Mesylate, Bivalirudin, Bizelesin, Bleomycin Sulfate, boldine, Bolandiol
Dipropionate, Bolasterone, Boldenone Undecylenate, Bolenol, Bolmantalate, bopindolol, Bosentan, Botulin toxin, Boxidine, brefeldin, breflate, Brequinar Sodium, Bretazenil, Bretylium Tosylate, Brifentanil Hydrochloride, brimonidine, Brinolase, Brocresine,
Brocrinat, Brofoxine, Bromadoline Maleate, Bromazepam, Bromchlorenone, Bromelain, bromfenac, Brominidione, Bromocriptine, Bromodiphenhydramine Hydrochloride,
Bromoxanide, Bromperidol, Bromperidol Decanoate, Brompheniramine Maleate,
Broperamole, Bropirimine, Brotizolam, Bucainide Maleate, bucindolol, Buclizine
Hydrochloride, Bucromar one, Budesonide, budipine, budotitane, Buformin, Bumetanide, Bunaprolast, bunazosin, Bunolol Hydrochloride, Bupicomide, Bupivacaine Hydrochloride, Buprenorphine, Buprenorphine Hydrochloride, Bupropion, bupropion hydrobromide, Bupropion Hydrochloride, Buramate, Buserelin Acetate, Buspirone Hydrochloride, Busulfan, Butabarbital, Butacetin, Butaclamol Hydrochloride, Butalbital, Butamben, Butamirate Citrate, Butaperazine, Butaprost, Butedronate Tetrasodium, butenafine, Buterizine, buthioninc sulfoximine, Butikacin, Butilfenin, Butirosin Sulfate, Butixirate, butixocort propionate, Butoconazole Nitrate, Butonate, Butopamine, Butoprozine Hydrochloride, Butorphanol, Butoxamine Hydrochloride, Butriptyline Hydrochloride, Cabergoline,
Cactinomycin, Cadexomer Iodine, Caffeine, calanolide A, Calcifediol, Calcipotriene, calcipotriol, Calcitonin, Calcitriol, Calcium Undecylenate, calphostin C, Calusterone, Cambendazole, Cammonam Sodium, camonagrel, canary pox IL-2, candesartan, candesartan cilexetil, Candicidin, candoxatril, candoxatrilat, Caniglibose, Canrenoate Potassium,
Canrenone, capecitabine, Capobenate Sodium, Capobenic Acid, Capreomycin Sulfate, capromab, capsaicin, Captopril, Capuride, Car bocysteine, Caracemide, Carbachol, Carbadox, Carbamazepine, Carbamide Peroxide, Carbantel Lauryl Sulfate, Carbaspirin Calcium, Carbazeran, carbazomycin C, Carbenicillin Potassium, Carbenoxolone Sodium, Carbetimer, carbetocin, Carbidopa, Carbidopa-Levodopa, Carbinoxamine Maleate, Carbiphene
Hydrochloride, Carbocloral, Carbol-Fuchsin, Carboplatin, Carboprost, carbovir,
carboxamide-amino-triazo-le, carboxyamidotriazole, carboxymethylated beta-l,3-glucan, arV p i w-i^ochloride, CaRest M3, Carfentanil Citrate, Carisoprodol, Carmantadine, Carmustine, CAR 700, Carnidazole, Caroxazone, carperitide, Carphenazine Maleate, Carprofen, Carsatrin Succinate, Cartazolate, carteolol, Carteolol Hydrochloride, Carubicin Hydrochloride, carvedilol, carvotroline, Carvotroline Hydrochloride, carzelesin,
Caspofungin, castanospermine, caurumonam, cebaracetam, cecropin B, Cedefingol, Cefaclor, Cefadroxil, Cefamandole, Cefaparole, Cefatrizine, Cefazaflur Sodium, Cefazolin, cefcapene pivoxil, cefdaloxime pentexil tosilate, Cefdinir, cefditoren pivoxil, Cefepime, cefetamet, Cefetecol, cefixime, cefluprenam, Cefmenoxime Hydrochloride, Cefmetazole, cefminlox, cefodizime, Cefonicid Sodium, Cefoperazone , Cefoperazone Sodium, Ceforanide, cefoselis, Cefotaxime Sodium, Cefotetan, cefotiam, Cefoxitin, cefozopran, cefpimizole, Cefpiramide, cefpirome, cefpodoxime proxetil, cefprozil, Cefroxadine, cefsulodin, Ceftazidime, cefteram, ceftibuten, Ceftizoxime Sodium, ceftriaxooe, Cefuroxime, celastrol, Celecoxib, celikalim, celiprolol, cepacidiine A, Cephacetrile Sodium, Cephalexin, Cephaloglycin, Cephaloridine, Cephalothin Sodium, Cephapirin Sodium, Cephradine, cericlamine, cerivastatin, Cernletide, Ceronapril, Certolizumab Pegol, certoparin sodium, Cetaben Sodium, Cetalkonium Chloride, Cetamolol Hydrochloride, Cethuperazone, cetiedil, cetirizine, Cetophenicol, Cetraxate
Hydrochloride, Cetrizine hydrochloride, cetrorelix, Cetuximab, Cetylpyridinium Chloride, Chenodiol, Chlophedianol Hydrochloride, Chloral Betaine, Chlorambucil, Chloramphenicol, Chlordantoin, Chlordiazepoxide, Chlorhexidine Gluconate, chlorins, Chlormadinone Acetate, chloroorienticin A, Chloroprocaine Hydrochloride, Chloropropamide, Chloroquine, chloroquinoxaline sulfonamide, Chlorothiazide, Chlorotrianisene, Chloroxine, Chloroxylenol, Chlorphe niramine Maleate, Chlorphenesin Carbamate, Chlorpheniramine maleate,
Chlorpromazine, Chlorpromazine hydrochloride, Chlorpropamide, Chlorprothixene,
Chlortetracycline Bisulfate, Chlorthalidone, Chlorzoxazone, Cholestyramine Resin,
Chromonar Hydrochloride, cibenzoline, cicaprost, Ciclafrine Hydrochloride, Ciclazindol, ciclesonide, cicletanine, Ciclopirox, Cicloprofen, cicloprolol, Cidofovir, Cidoxepin
Hydrochloride, Cifenline, Ciglitazone, Ciladopa Hydrochloride, cilansetron, Cilastatin, Cilastatin Sodium, Cilazapril, cilnidipine, Cilobamine Mesylate, cilobradine, Cilofungin, cilostazol, Cimaterol, Cimetidine, cimetropium bromide, Cinacalcet, Cinalukast, Cinanserin Hydrochloride, Cinepazet Maleate, Cinflumide, Cingestol, cinitapride, Cinnamedrine, Cinnarizine, cinolazepam, Cinoxacin, Cinperene, Cinromide, Cintazone, Cintriamide, Ciot eronel, Cipamfylline, Ciprefadol Succinate, Ciprocinonide, Ciprofibrate, Ciprofloxacin, ciprostene, Ciramadol, Cirolemycin, Cis platin, cisapride, cisatracurium besilate,
Cisconazole, cis-porphyrin, cistinexine, citalopram, citalopram hydrobromide, Citenamide, ^;+;™i + < rmc alpha, cladribine, Clamoxyquin Hydrochloride, Clarithromycin, clausenamide, Clavulanate Potassium, Clazolam, Clazolimine, clebopride, Clemastine, Clentiazem Maleate, Clidinium Bromide, clinafloxacin, Clindamycin, clindamycin hydrochloride, Clioquinol, Clioxanide, Cliprofen, clobazam, Clobetasol Propionate, Clobetasone Butyrate, Clocortolone Acetate, Clodanolene, Clodazon Hydrochloride, clodronic acid, Clofazimine, Clofibrate, Clofilium Phosphate, Cloge stone Acetate,
Clomacran Phosphate, Clomegestone Acetate, Clometherone, clomethiazole, clomifene ana logues, Clominorex, Clomiphene, Clomipramine Hydrochloride, Clonazepam, Clonidine, Clonidine hydrochloride, Clonitrate, Clonixeril, Clonixin, Clopamide, Clopenthixol, Cloperidone Hydrochloride, clopidogrel, Clopidogrel bisulfate, Clopimozide, Clopipazan Mesylate, Clopirac, Cloprednol, Cloprostenol Sodium, Clorazepate Dipotassium, Clorethate, Clorexolone, Cloroperone Hydrochloride, Clorprenaline Hydrochloride, Clorsulon,
Clortemine Hydrochloride, Closantel, Closiramine Aceturate, Clothiapine, Clothixamide Maleate Cloticasone Propionate, Clotrimazole, Cloxacillin Benzathine, Cloxacillin Sodium, Cloxyquin, Clozapine, Co-Amoxiclav, Cocaine, Coccidioidin, Codeine, Codeine phosphate, Codoxime, Colchicine, Colesevelam, colestimide, Colestipol Hydrochloride, Colestolone, Colforsin, Colfosceril Palmitate, Colistimethate Sodium, Colistin Sulfate, collismycin A, collismycin B, Colterol Mesylate, combretastatin A4, complestatin, conagenin, Conorphone Hydrochloride, contignasterol, contortrostatin, Cormethasone Acetate, Corticorelin Ovine Tnflutate, Corticotropin, Cortisone Acetate, Cortivazol, Cortodoxone, cosalane, costatolide, Cosyntropin, cotinine, Coumadin, Coumermycin, crambescidin, Crilvastatin, crisnatol, Cromitrile Sodium, Cromolyn Sodium, Crotamiton, cryptophycin, cucumariosid,
Cuprimyxin, curacin A, curdlan sulfate, curiosin, Cyclacillin, Cyclazocine, cyclazosin, Cyclindole, Cycliramine Maleate, Cyclizine, Cyclobendazole, cyclobenzaprine,
cyclobenzaprine hydrochloride, cyclobut A, cyclobut G, cyclocapron, Cycloguanil Pamoate, Cycloheximide, cyclopentanthraquinones, Cyclopenthiazide, Cyclopentolate Hydrochloride, Cyclophenazine Hydrochloride, Cyclophosphamide, cycloplatam, Cyclopropane,
Cycloserine, cyclosin, Cyclosporine, cyclothialidine, Cyclothiazide, cyclothiazomycin, Cyheptamide, cypemycin, Cyponamine Hydrochloride, Cyprazepam, Cyproheptadine Hydrochloride, Cyprolidol Hydrochloride, cyproterone, Cyproximide, Cysteamine, Cysteine Hydrochloride, Cystine, Cytarabine, Cytarabine Hydrochloride, cytarabine ocfosfate, cytochalasin B, cytostatin, Dacarbazine, dacliximab, dactimicin, Dactinomycin, daidzein, Daledalin Tosylate, dalfopristin, Dalteparin Sodium, Daltroban, Dalvastatin, danaparoid, Danazol, Dantrolene, daphlnodorin A, dapiprazole, dapitant, Dapoxetine Hydrochloride, nQniAn,s nQ"+^mycin, darbepoetin alfa, Darglitazone Sodium, darifenacin, darlucin A, Darodipine, darsidomine, Daunornbicin Hydrochloride, Dazadrol Maleate, Dazepinil Hydrochloride, Dazmegrel, Dazopride Fumarate, Dazoxiben Hydrochloride, DCRM 197 protein, Debrisoquin Sulfate, Decitabine, deferiprone, deflazacort, Dehydrocholic Acid, dehydrodidemnin B, Dehydroepiandrosterone, delapril, Delapril Hydrochloride, Delavirdine Mesylate, delequamine, delfaprazine, Delmadinone Acetate, delmopinol, delphinidin, Demecarium Bromide, Demeclocycline, Demecycline, Demoxepam, Denofungin, deoxypyridinoline, Depakote, deprodone, Deprostil, depsidomycin, deramciclane, dermatan sulfate, Desciclovir, Descinolone Acetonide, Desfiurane, Desipramine Hydrochloride, desirudin, Deslanoside, Desloratadine, deslorelin, desmopressin, Desmopressin sulfate, desogestrel, Desonide, Desoximetasone, desoxoamiodarone, Desoxy-corticosterone Acetate, detajmium bitartrate, Deterenol Hydrochloride, Detirelix Acetate, Devazepide,
Dexamethasone, Dexamisole, Dexbrompheniramine Maleate, Dexchlorpheniramine Maleate, Dexclamol Hydrochloride, Dexetimide, Dexfenfluramine Hydrochloride, dexifosfamide, Deximafen, dexketoprofen, dexloxiglumide, Dexmedetomidine, Dexormaplatin, Dexoxadrol Hydrochloride, Dexpanthenol, Dexpemedolac, Dexpropranolol Hydrochloride, Dexrazoxane, dexsotalol, dextrin 2-sulphate, Dextroamphetamine, Dextromethorphan, Dextrorphan Hydrochloride, Dextrothyroxine Sodium, dexverapamil, Dezaguanine, dezinamide, dezocine, Diacetolol Hydrochloride, Diamocaine Cyclamate, Diapamide, Diatrizoate Meglumine, Diatrizoic Acid, Diaveridine, Diazepam, Diaziquone, Diazoxide, Dibenzepin Hydrochloride, Dibenzothiophene, Dibucaine, Dichliorvos, Dichloralphenazone, Dichlorphenamide,
Dicirenone, Diclofenac, Diclofenac Sodium, Dicloxacillin, dicranin, Dicumarol, Dicyclomine Hydrochloride, Didanosine, didemnin B, didox, Dienestrol, dienogest, Diethylcarbamazine Citrate, diethylhomospermine, diethylnorspermine, Diethylpropion Hydrochloride,
Diethylstilbestrol, Difenoximide Hydrochloride, Difenoxin, Diflorasone Diacetate,
Difloxacin Hydrochloride, Difluanine Hydrochloride, Diflucortolone, Diflumidone Sodium, Diflunisal, Difluprednate, Diftalone, Digitalis, Digitoxin, Digoxin, Dihexyverine
Hydrochloride, dihydrexidine, dihydro-5-azacytidine, Dihydrocodeine Bitartrate,
Dihydroergotamine Mesylate, Dihydroestosterone, Dihydrostreptomycin Sulfate,
Dihydrotachysterol, Dilantin, Dilevalol Hydrochloride, Diltiazem Hydrochloride,
Dimefadane, Dimefline Hydrochloride, Dimenhydrinate, Dimercaprol, Dimethadione, Dimethindene Maleate, Dimethisterone, Dimethyl Sulfoxide, dimethylhomospermine, dimethylprostaglandin Al, dimiracetam, Dimoxamine Hydrochloride, Dinoprost,
Dinoprostone, Dioxadrol Hydrochloride, dioxamycin, diphenhydramine, Diphenhydramine ;+ratp Diphenoxylate Hydrochloride, diphenylspiromustine, Dipivefin Hydrochloride, Dipivefrin, dipliencyprone, diprafenone, dipropylnorspermine, Dipyridamole, Dipyrithione, Dipyrone, dirithromycin, discodermolide, Disobutamide, Disofenin,
Disopyramide, Disoxaril, disulfiram, Ditekiren, Divalproex Sodium, Dizocilpine Maleate, DL-methionine, Dobutamine, docarpamine, Docebenone, Docetaxel, Doconazole, docosanol, dofetilide, dolasetron, Donepezil, doripenem, Dorzolamide, Doxazosin, doxazosin mesylate, doxycydine, Drospirenone, Duloxetine, Dutasteride, Ebastine, ebiratide, ebrotidine, ebselen, ecabapide, ecabet, ecadotril, ecdisteron, echicetin, echistatin, Echothiophate Iodide,
Eclanamine Maleate, Eclazolast, ecomustine, Econazole, ecteinascidin 722, eculizumab, edaravone, Edatrexate, edelfosine, Edifolone Acetate, edobacomab, Edoxudine, edrecolomab, Edrophonium Chloride, edroxyprogesteone Acetate, Efavirenz, efegatran, eflornithine, efonidipine, egualcen, Elantrine, eleatonin, elemene, eletriptan, elgodipine, eliprodil, Elsamitrucin, eltenae, Elucaine, emailcalim, emedastine, Emetine Hydrochloride, emiglitate, Emilium Tosylate, emitefur, emoctakin, Emtricitabine, Enadoline Hydrochloride, Enailciren, enalapril, enalapril maleate, enazadrem, Encyprate, Endralazine Mesylate, Endrysone, Enflurane, englitazone, Enilconazole, Enisoprost, Enlimomab, Enloplatin, Enofelast,
Enolicam Sodium, Enoxacin, enoxacin, enoxaparin sodium, Enoxaparin Sodium, Enoximone, Enpiroline Phosphate, Enprofylline, Enpromate, entacapone, enterostatin, Enviradene, Enviroxime, Ephedrine, Epicillin, Epimestrol, Epinephrine, Epinephryl Borate, Epipropidine, Epirizole, epirubicin, Epitetracycline Hydrochloride, Epithiazide, Epoetin Alfa, Epoetin Beta, Epoprostenol, Epoprostenol Sodium, epoxymexrenone, epristeride, Eprosartan, eptastigmine, equilenin, Equilin, Erbulozole, erdosteine, Ergoloid Mesylates, Ergonovine Maleate, Ergotamine Tartrate, Erlotinib, ersentilide, Ersofermin, erythritol, Erythrityl Tetranitrate, Erythromycin, Erythropoetin, Escitalopram, Esmolol Hydrochloride, esomeprazole,
Esorubicin Hydrochloride, Esproquin Hydrochloride, Estazolam, Estradiol, Estramustine, Estrazinol Hydrobromide, Estriol, Estrofurate, Estrogen, Estrone, Estropipate, esuprone, Eszopiclone, Etafedrine Hydrochloride, etanercept, Etanidazole, etanterol, Etarotene, Etazolate Hydrochloride, Eterobarb, ethacizin, Ethacrynate Sodium, Ethacrynic Acid, Ethambutol Hydrochloride, Ethamivan, Ethanolamine Oleate, Ethehlorvynol, Ethembutol hydrochloride, Ethinyl estradiol, Ethiodized Oil, Ethionamide, Ethonam Nitrate,
Ethopropazine Hydrochloride, Ethosuximide, Ethosuximide, Ethotoin, Ethoxazene
Hydrochloride, Ethybenztropine, Ethyl Chloride, Ethyl Dibunate, Ethylestrenol, Ethyndiol, Ethynerone, ethynl estradiol, Ethynodiol Diacetate, Etibendazole, Etidocaine, Etidronate Disodium, Etidronic Acid, Etifenin, Etintidine Hydrochloride, etizolam, Etodolac,
BtAfffn amatP ^+oformin Hydrochloride, Etomidate, Etonogestrel, Etoperidone Hydrochloride, Etoposide, Etoprine, etoricoxib, Etoxadrol Hydrochloride, Etozolin, etrabamine, etravirine, Etretinate, Etryptamine Acetate, Eucatropine Hydrochloride, Eugenol, Euprocin Hydrochloride, eveminomicin, Exametazime, examorelin, Exaprolol
Hydrochloride, exemestane, Exenatide, Ezetimibe, Ezetimibe, Factor VII, fadrozole, faeriefungin, Famciclovir, Famotidine, Fampridine, fantofarone, Fantridone Hydrochloride, faropenem, fasidotril, fasudil, fazarabine, fedotozine, Felbamate, felbamate, Felbinac, Felodipine, Felypressin, Fenalamide, Fenamole, Fenbendazole, Fenbufen, Fencibutirol, Fenclofenac, Fenclonine, Fenclorac, Fendosal, Fenestrel, Fenethylline Hydrochloride, Fenfluramine Hydrochloride, Fengabine, Fenimide, Fenisorex, Fenmetozole Hydrochloride, Fenmetramide, Fenobam, Fenoctimine Sulfate, Fenofibrate, fenoldopam, Fenoprofen,
Fenoterol, Fenpipalone, Fenprinast Hydrochloride, Fenprostalene, Fenquizone, fenretinide, fenspiride, fentanyl, Fentanyl Citrate, Fentiazac, Fenticlor, fenticonazole, Fenyripol
Hydrochloride, fepradinol, ferpifosate sodium, ferristene, ferrixan, Ferrous Sulfate,
Ferumoxides, ferumoxsil, Fetoxylate Hydrochloride, Fexofenadine, fexofenadine
hydrochloride, Fezolamine Fumarate, Fiacitabine, Fialuridine, fibmoxef, Fibrinogen,
Filgrastim, Filipin, Finasteride, fiorfenicol, fiorifenine, fiosatidil, fiumecinol, fiunarizine, fiuparoxan, fiupirtine, fiurithromycin, fiutrimazole, fiuvastatin, fiuvoxamine, Flavodilol Maleate, flavopiridol, Flavoxate Hydrochloride, Flazalone, flecainide, flerobuterol,
Fleroxacin, flesinoxan, Flestolol Sulfate, Fletazepam, flezelastine, flobufen, Floctafenine, Flordipine, Flosequinan, Floxacillin, Floxuridine, fluasterone, Fluazacort, Flubanilate Hydrochloride, Flubendazole, Flucindole, Flucloronide, Fluconazole, Flucytosine,
Fludalanine, Fludarabine Phosphate, Fludazonium Chloride, Fludeoxyglucose, Fludorex, Fludrocortisone Acetate, Flufenamic Acid, Flufenisal, Flumazenil, Flumequine, Flumeridone, Flumethasone, Flumetramide, Flumezapine, Fluminorex, Flumizole, Flumoxonide,
Flunidazole, Flunisolide, Flunitrazepam, Flunixin, fluocalcitriol, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone, Fluorescein, fluorodaunorunicin
hydrochloride, Fluorodopa, Fluorometholone, Fluorouracil, Fluotracen Hydrochloride, Fluoxetine, Fluoxetine hydrochloride, Fluoxymesterone, Fluperamide, Fluperolone Acetate, Fluphenazine Decanoate, Fluprednisolone, Fluproquazone, Fluprostenol Sodium,
Fluquazone, Fluradoline Hydrochloride, Flurandrenolide, Flurazepam Hydrochloride, Flurbiprofen, Fluretofen, Flurocitabine, Flurofamide, Flurogestone Acetate, Flurothyl, Fluroxene, Fluspiperone, Fluspirilene, Fluticasone, Fluticasone Propionate, Flutroline, Fiuvastatin, Fiuvastatin Sodium, Fluzinamide, Folic Acid, Follicle regulatory protein,
T^ii; ,i ta+;« ^ollitropin alfa, Follitropin beta, Fomepizole, Fonazine Mesylate, forasartan, forfenimex, forfenirmex, formestane, Formocortal, formoterol, Fosarilate, Fosazepam, Foscarnet Sodium, fosfomycin, Fosfonet Sodium, fosinopril, Fosinopril sodium, Fosinoprilat, fosphenytoin, Fosquidone, Fostedil, fostriecin, fotemustine, Fuchsin, Fumoxicillin,
Fungimycin, Furaprofen, Furazolidone, Furazolium Chloride, Furegrelate Sodium,
Furobufen, Furodazole, Furosemide, Fusidate Sodium, Fusidic Acid, Gabapentin,
Gadobenate Dimeglumine, gadobenic acid, gadobutrol, Gadodiamide, gadolinium texaphyrin, Gadopentetate Dimegiumine, gadoteric acid, Gadoteridol, Gadoversetamide, galantamine, galdansetron, Galdansetron Hydrochloride, Gallamine Triethiodide, gallium nitrate, gallopamil, galocitabine, Gamfexine, gamolenic acid, Ganciclovir, ganirelix, Gemcadiol, Gemcitabine, Gemeprost, Gemfibrozil, Gentamicin Sulfate, Gentian Violet, gepirone, Gestaclone, Gestodene, Gestonorone Caproate, Gestrinone, Gevotroline Hydrochloride, girisopam, glargine insulin, glaspimod, Glatiramer, glaucocalyxin A, Glemanserin,
Gliamilide, Glibornuride, Glicetanile Sodium, Glifiumide, Glimepiride, Glipizide,
Gloximonam, Glucagon, glutapyrone, Glutethimide, Glyburide, glycopine, glycopril, Glycopyrrolate, Glyhexamide, Glymidine Sodium, Glyoctamide, Glyparamide, Gold Au-198, Gonadoctrinins, Gonadorelin, Gonadotropins, Goserelin, Gramicidin, Granisetron, grepafioxacin, Griseofulvin, Guaiapate, Guaithylline, Guanabenz, Guanabenz Acetate, Guanadrel Sulfate, Guancydine, Guanethidine Monosulfate, Guanfacine Hydrochloride, Guanisoquin Sulfate, Guanoclor Sulfate, Guanoctine Hydrochloride, Guanoxabenz,
Guanoxan Sulfate, Guanoxyfen Sulfate, Gusperimus Trihydrochloride, Halazepam,
Halcinonide, halichondrin B, Halobetasol Propionate, halofantrine, Halofantrine
Hydrochloride, Halofenate, Halofuginone Hydrobromide, halomon, Halopemide,
Haloperidol, halopredone, Haloprogesterone, Haloprogin, Halothane, Halquinols, Hamycin, hatomamicin, hatomarubigin A, hatomarubigin B, hatomarubigin C, hatomarubigin D, Heparin Sodium, hepsulfam, heregulin, Hetacillin, Heterooium Bromide, Hexachlorophene :Hydrogen Peroxide, Hexafluorenium Bromide, hexamethylene bisacetamide, Hexedine, Hexobendine, Hexoprenaline Sulfate, Hexylresorcinol, Histamine Phosphate, Histidine, Histoplasmin, Histrelin, histrelin acetate, Homatropine Hydrobromide, Hoquizil
Hydrochloride, Human chorionic gonadotropin, Human growth hormone, Hycanthone, Hydralazine Hydrochloride, Hydralazine Polistirex, Hydrochlorothiazide, Hydrocodone Bitartrate, Hydrocortisone, Hydroflumethiazide, Hydromorphone Hydrochloride,
Hydroxyamphetamine Hydrobromide, Hydroxychloroquine Sulfate, Hydroxyphenamate, Hydroxyprogesterone Caproate, Hydroxyurea, Hydroxyzine Hydrochloride, Hymecromone, HmcTOQminp hypericin, Ibafloxacin, Ibandronate, ibogaine, Ibopam, ibudilast, Ibufenac, Ibuprofen, Ibutilide Fumarate, Icatibant Acetate, Ichthammol, Icotidine, idarubicin, idoxifene, Idoxuridine, idramantone, Ifetroban, Ifosfamide, Ilepeimide, illimaquinone, ilmofosin, ilomastat, Ilonidap, iloperidone, iloprost, Imafen Hydrochloride, Imatinib, Imazodan Hydrochloride, imidapril, imidazenil, imidazoacridone, Imidecyl Iodine, Imidocarb Hydrochloride, Imidoline Hydrochloride, Imidurea, Imiglucerase, Imiloxan Hydrochloride, Imipenem, Imipramine Hydrochloride, imiquimod, Impromidine Hydrochloride, Indacrinone, Indapamide, Indecainide Hydrochloride, Indeloxazine Hydrochloride, Indigotindisulfonate Sodium, indinavir, Indinavir sulfate, Indocyanine Green, Indolapril Hydrochloride, Indolidan, indometacin, Indomethacin Sodium, Indoprofen, indoramin, Indorenate Hydrochloride, Indoxole, Indriline Hydrochloride, infliximab, inocoterone, inogatran, inolimomab, Inositol Niacinate, Insulin, Interferon beta- la, Intrazole, Intriptyline Hydrochloride, iobenguane, Iobenzamic Acid, iobitridol, Iodine, iodoamiloride, iododoxorubicin, iofratol, iomeprol, iopentol, iopromide, iopyrol, iotriside, ioxilan, ipazilide, ipenoxazone, ipidacrine, Ipodate Calcium, ipomeanol, Ipratropium, Ipratropium Bromide, ipriflavone, Iprindole, Iprofenin, Ipronidazole, Iprop latin, Iproxamine Hydrochloride, ipsapirone, irbesartan, irinotecan, irloxacin, iroplact, irsogladin, Irtemazole, isalsteine, Isamoxole, isbogrel, Isepamicin, isobengazole, Isobutamben, Isocarboxazid, Isoconazole, Isoetharine, isofloxythepin,
Isoflupredone Acetate, Isoflurane, Isoflurophate, isohomohalicondrin B, Isoleucine,
Isomazole Hydrochloride, Isomylamine Hydrochloride, Isoniazid, Isopropamide Iodide, Isopropyl Alcohol, isopropyl unoprostone, Isoproterenol Hydrochloride, Isosorbide,
Isosorbide Mononitrate, Isotiquimide, Isotretinoin, Isoxepac, Isoxicam, Isoxsuprine
Hydrochloride, isradipine, itameline, itasetron, Itazigrel, itopride, Itraconazole, Ivermectin, ixabepilone, jasplakinolide, Jemefloxacin, Jesopitron, Josamycin, kahalalide F, Kalafungin, Kanamycin Sulfate, ketamine, Ketanserin, Ketazocine, Ketazolam, Kethoxal, Ketipramine Fumarate, Ketoconazole, Ketoprofen, Ketorfanol, ketorolac, Ketotifen Fumarate,
Kitasamycin, Labetalol Hydrochloride, Lacidipine, lacidipine, lactitol, lactivicin,
Lactobionate, laennec, lafutidine, 1-alphahydroxyvitamin D2, lamellarin-N triacetate, lamifiban, Lamivudine, Lamotrigine, lanoconazole, Lanoxin, lanperisone, lanreotide, lanreotide acetate, Lansoprazole, lapatinib, laropiprant, latanoprost, lateritin, laurocapram, Lauryl Isoquinolinium Bromide, Lavoltidine Succinate, lazabemide, Lecimibide, leinamycin, lemildipine, leminoprazole, lenercept, Leniquinsin, lenograstim, Lenperone, lentinan sulfate, leptin, leptolstatin, lercanidipine, Lergotrile, lerisetron, Letimide Hydrochloride, letrazuril, letrozole, Leucine, leucomyzin, leuprolide, Leuprolide Acetate, leuprorelin, Levalbuterol, T m/QinfctQminp Succinate, levamisole, Levdobutamine Lactobionate, Leveromakalim, levetiracetam, Leveycloserine, levobetaxolol, levobunolol, levobupivacaine, levocabastine, levocarnitine, levocetirizine, levocetirizine dihydrochloride, Levodopa, levodropropizine, levofloxacin, Levofuraltadone, Levoleucovorin Calcium, Levomethadyl Acetate,
Levomethadyl Acetate Hydrochloride, levomoprolol, Levonantradol Hydrochloride, Levonordefrin, Levonorgestrel, Levopropoxyphene Napsylate, Levopropylcillin Potassium, levormeloxifene, Levorphanol Tartrate, levosimendan, levosulpiride, Levothyroxine, Levothyroxine Sodium, Levoxadrol Hydrochloride, Lexipafant, Lexithromycin, liarozole, Libenzapril, Lidamidine Hydrochloride, Lidocaine, Lidofenin, Lidoflazine, Lifarizin, Lifibrate, Lifibrol, Linarotene, Lincomycin, Linezolid, Linogliride, Linopirdine, linotroban, linsidomine, lintitript, lintopride, Liothyronine 1-125, liothyronine sodium, Liotrix, lirexapride, Lisdexamfetamine Dimesylate, lisinopril, Lispro insulin, lissoclinamide, Lixazinone Sulfate, lobaplatin, Lobenzarit Sodium, Lobucavir, locarmate Meglumine, locarmic Acid, locetamic Acid, lodamide, Lodelaben, lodipamide Meglumine, lodixanol, lodoantipyrine 1-131, lodocholesterol 1-131, lodohippurate Sodium 1-131, lodopyracet 1-125, lodoquinol, lodoxamate Meglumine, lodoxamide, lodoxamie Acid, Lofemizole
Hydrochloride, Lofentanil Oxalate, Lofepramine Hydrochloride, lofetamine Hydrochloride I- 123, Lofexidine Hydrochloride, loglicic Acid, loglucol, loglucomide, loglycamic Acid, logulamide, lohexol, lombricine, Lomefloxacin, lomerizine, lomethin 1-125, Lometraline Hydrochloride, lometrexol, Lomofungin, Lomoxicam, Lomustine, Lonapalene, lonazolac, lonidamine, lopamidol, lopanoic Acid, Loperamide Hydrochloride, lophendylate, Lopinavir, loprocemic Acid, lopronic Acid, lopydol, lopydone, loracarbef, Lorajmine Hydrochloride, loratadine, Lorazepam, Lorbamate, Lorcainide Hydrochloride, Loreclezole, Loreinadol, lorglumide, Lormetazepam, Lornoxicam, lornoxicam, Lortalamine, Lorzafone, losartan, Losartan potassium, losefamic Acid, loseric Acid, losigamone, losoxantrone, losulamide Meglumine, Losulazine Hydrochloride, losumetic Acid, lotasul, loteprednol, lotetric Acid, lothalamate Sodium, lothalamic Acid, lotrolan, lotroxic Acid, lovastatin, loversol, loviride, loxagiate Sodium, loxaglate Meglumine, loxaglic Acid, Loxapine, Loxoribine, loxotrizoic Acid, lubeluzole, Lucanthone Hydrochloride, Lufironil, Lurosetron Mesylate, lurtotecan, lutetium, Lutrelin Acetate, luzindole, Lyapolate Sodium, Lycetamine, lydicamycin,
Lydimycin, Lynestrenol, Lypressin, Lysine, lysofylline, lysostaphin, Maduramicin,
Mafenide, magainin 2 amide, Magnesium Salicylate, Magnesium Sulfate, magnolol, maitansine, Malethamer, mallotoaponin, mallotochromene, Malotilate, malotilate, mangafodipir, manidipine, maniwamycin A, Mannitol, mannostatin A, manumycin E, ma™,!/ v rnapinastine, Maprotiline, maraviroc, marimastat, Marinol, Masoprocol, maspin, massetolide, Maytansine, Mazapertine Succiniate, Mazindol, Mebendazole, Mebeverine Hydrochloride, Mebrofenin, Mebutamate, Mecamylamine Hydrochloride, Mechlorethamine Hydrochloride, meclizine hydrochloride, Meclocycline, Meclofenamate Sodium, Mecloqualone, Meclorisone Dibutyrate, Medazepam Hydrochloride, Medorinone, Medrogestone, Medroxalol, Medroxyprogesterone, Medrysone, Meelizine Hydrochloride, Mefenamic Acid, Mefenidil, Mefenorex Hydrochloride, Mefexamide, Mefloquine
Hydrochloride, Mefruside, Megalomicin Potassium Phosphate, Megestrol Acetate,
Meglumine, Meglutol, Melengestrol Acetate, Meloxicam, Melphalan, Memantine, Memotine Hydrochloride, Menabitan Hydrochloride, Menoctone, menogaril, Menotropins, Meobentine Sulfate, Mepartricin, Mepenzolate Bromide, Meperidine Hydrochloride, Mephentermine Sulfate, Mephenytoin, Mephobarbital, Mepivacaine Hydrochloride, Meprobamate,
Meptazinol Hydrochloride, Mequidox, Meralein Sodium, merbarone, Mercaptopurine, Mercufenol Chloride, Merisoprol, Meropenem, Mesalamine, Meseclazone, Mesoridazine, Mesterolone, Mestranol, Mesuprine Hydrochloride, Metalol Hydrochloride, Metaproterenol Polistirex, Metaraminol Bitartrate, Metaxalone, Meteneprost, meterelin, Metformin, Methacholine Chloride, Methacycline, methadone, Methadyl Acetate, Methalthiazide, Methamphetamine Hydrochloride, Methaqualone, Methazolamide, Methdilazine,
Methenamine, Methenolone Acetate, Methetoin, Methicillin Sodium, Methimazole, methioninase, Methionine, Methisazone, Methixene Hydrochloride, Methocarbamol, Methohexital Sodium, Methopholine, Methotrexate, Methotrimeprazine, methoxatone, methoxy polyethylene glycol-epoetin beta, Methoxyflurane, Methsuximide,
Methyclothiazide, Methyl Palmoxirate, Methylatropine Nitrate, Methylbenzethonium Chloride, Methyldopa, Methyldopate Hydrochloride, Methylene Blue, Methylergonovine Maleate, methylhistamine, methylinosine monophosphate, Methylphenidate,
Methylprednisolone, Methyltestosterone, Methynodiol Diacelate, Methysergide,
Methysergide Maleate, Metiamide, Metiapine, Metioprim, metipamide, Metipranolol, Metizoline Hydrochloride, Metkephamid Acetate, metoclopramide, Metocurine Iodide, Metogest, Metolazone, Metopimazine, Metoprine, Metoprolol, Metoprolol tartrate,
Metouizine, metrifonate, Metrizamide, Metrizoate Sodium, Metronidazole, Meturedepa, Metyrapone, Metyrosine, Mexiletine Hydrochloride, Mexrenoate Potassium, Mezlocillin,
Mianserin Hydrochloride, mibefradil, Mibefradil Dihydrochloridc, Mibolerone, michellamine B, Miconazole, microcolin A, Midaflur, Midazolam Hydrochloride, midodrine, mifepristone, Mifobate, miglitol, milacemide, milameline, mildronate, Milenperone, Milipertine,
miinQ rnran ^^rinone, miltefosine, Mimbane Hydrochloride, minaprine, Minaxolone, Minocromil, Minocycline, Minocycline hydrochloride, Minoxidil, Mioflazine Hydrochloride, miokamycin, mipragoside, mirfentanil, mirimostim, Mirincamycin Hydrochloride, Mirisetron Maleate, Mirtazapine, Misonidazole, Misoprostol, Mitindomide, Mitocarcin, Mitocromin, Mitogillin, mitoguazone, mitolactol, Mitomalcin, Mitomycin, mitonafide, Mitosper,
Mitotane, mitoxantrone, mivacurium chloride, mivazerol, mixanpril, Mixidine, mizolastine, mizoribine, Moclobemide, modafinil, Modaline Sulfate, Modecainide, moexipril, mofarotene, Mofegiline Hydrochloride, mofezolac, molgramostim, Molinazone, Molindone
Hydrochloride, Molsidomine, mometasone, Monatepil Maleate, Monensin, Monoctanoin, montelukast, Montelukast Sodium, montirelin, mopidamol, moracizine, Morantel Tartrate, Moricizine, Morniflumate, Morphine, Morrhuate Sodium, mosapramine, mosapride, motilide, Motretinide, Moxalactam Disodium, Moxazocine, Moxifloxacin, moxiraprine, Moxnidazole, moxonidine, Mumps Skin Test Antigen, Muzolimine, mycaperoxide B, Mycophenolate mofetil, Mycophenolic Acid, myriaporone, Nabazenil, Nabilone, Nabitan Hydrochloride, Naboctate Hydrochloride, Nabumetone, N-acetyldinaline, Nadide, nadifloxacin, Nadolol, nadroparin calcium, nafadotride, nafamostat, nafarelin, Nafcillin Sodium, Nafenopin, Nafimidone Hydrochloride, Naflocort, Nafomine Malate, Nafoxidine Hydrochloride, Nafronyl Oxalate, Naftifine Hydrochloride, naftopidil, naglivan, nagrestip, Nalbuphine Hydrochloride, Nalidixate Sodium, Nalidixic Acid, nalmefene, Nalmexone Hydrochloride, naloxone, Naltrexone, Namoxyrate, Nandrolone Phenpropionate, Nantradol Hydrochloride, Napactadine Hydrochloride, napadisilate, Napamezole Hydrochloride, napaviin, Naphazoline Hydrochloride, naphterpin, Naproxen, Naproxen sodium, Naproxol, napsagatran, Naranol Hydrochloride, Narasin, naratriptan, nartograstim, nasaruplase, natalizumab, Natamycin, nateplase, Naxagolide Hydrochloride, Nebivolol, Nebramycin, nedaplatin, Nedocromil, Nefazodone Hydrochloride, Neflumozide Hydrochloride, Nefopam Hydrochloride,
Nelezaprine Maleate, Nemazoline Hydrochloride, nemorubicin, Neomycin Palmitate, Neostigmine Bromide, neridronic acid, Netilmicin Sulfate, Neutramycin, Nevirapin
Nexeridine Hydrochloride, Niacin, Nibroxane, Nicardipine Hydrochloride, Nicergoline, Niclosamide, Nicorandil, Nicotinamide, Nicotinyl Alcohol, Nifedipine, Nifirmerone, Nifluridide, Nifuradene, Nifuraldezone, Nifuratel, Nifuratrone, Nifurdazil, Nifurimide, Nifurpirinol, Nifurquinazol, Nifurthiazole, Nifurtimox, nilotinib, nilotinib hydrochloride monohydrate, nilutamide, Nilvadipine, Nimazone, Nimodipine, niperotidine, niravoline, Niridazole, nisamycin, Nisbuterol Mesylate, nisin, Nisobamate, Nisoldipine, Nisoxetin Nisterime Acetate, Nitarsone, nitazoxanide, nitecapone, Nitrafudam Hydrochloride,
Mitrai aminp w^rochloride, Nitramisole Hydrochloride, Nitrazepam, Nitrendipine, Nitrocydine, Nitrodan, Nitrofurantoin, Nitrofurazone, Nitroglycerin, Nitromersol, Nitromide, Nitromifene Citrate, Nitrous Oxide, nitroxide antioxidant, nitrullyn, Nivazol, Nivimedone Sodium, Nizatidine, Noberastine, Nocodazole, Nogalamycin, Nolinium Bromide,
Nomifensine Maleate, Noracymethadol Hydrochloride, Norbolethone, Norepinephrine Bitartrate, Norethindrone, Norethynodrel, Norfiurane, Norfloxacin, Norgestimate,
Norgestomet, Norgestrel, Nortriptyline Hydrochloride, Noscapine, Novobiocin Nylestriol, Nystatin, Obidoxime Chloride, Ocaperidone, Ocfentanil Hydrochloride, Ocinaplon, Octanoic Acid, Octazamide, Octenidine Hydrochloride, Octodrine, Octreotide, Octriptyline Phosphate, Ofloxacin, Ofornine, okicenone, Olanzepine, Olmesartan, olmesartan medoxomil, olopatadine, olopatadine hydrochloride, olprinone, olsalazine, Olsalazine Sodium, Olvanil, Omalizumab, Omega-3 acid ethyl esters, omeprazole, onapristone, ondansetron, Ontazolast, Oocyte Opipramol Hydrochloride, oracin, Orconazole Nitrate, Orgotein, Orlislat, Ormaplatin, Ormetoprim, Ornidazole, Orpanoxin, Orphenadrine Citrate, osaterone, Oseltamivir, otenzepad, Oxacillin Sodium, Oxagrelate, oxaliplatin, Oxamarin Hydrochloride, oxamisole, Oxamniquine, oxandrolone, Oxantel Pamoate, Oxaprotiline Hydrochloride, Oxaprozin, Oxarbazole, Oxatomide, oxaunomycin, Oxazepam, oxcarbazepine, Oxendolone,
Oxethazaine, Oxetorone Fumarate, Oxfendazole, Oxfenicine, Oxibendazole, oxiconazole, Oxidopamine, Oxidronic Acid, Oxifungin Hydrochloride, Oxilorphan, Oximonam,
Oximonam Sodium, Oxiperomide, oxiracetam, Oxiramide, Oxisuran, Oxmetidine
Hydrochloride, oxodipine, Oxogestone Phenopropionate, Oxolinic Acid, Oxprenolol
Hydrochloride, Oxtriphylline, Oxybutynin Chloride, Oxychlorosene, Oxycodone, oxycodone hydrochloride, Oxymetazoline Hydrochloride, oxymetholone, Oxymorphone Hydrochloride, Oxypertine, Oxyphenbutazone, Oxypurinol, Oxytetracycline, Oxytocin, ozagrel, Ozlinone, Paclitaxel, palauamine, Paldimycin, palinavir, Palivizumab, palmitoylrhizoxin, Palmoxirate Sodium, pamaqueside, Pamatolol Sulfate, pamicogrel, Pamidronate Disodium, pamidronic acid, Panadiplon, panamesine, panaxytriol, Pancopride, Pancuronium Bromide, panipenem, pannorin, panomifene, pantethine, pantoprazole, Papaverine Hydrochloride, parabactin, paracetamol, Parachlorophenol, Paraldehyde, Paramethasone Acetate, Paranyline
Hydrochloride, Parapenzolate Bromide, Pararosaniline Pamoate, Parbendazole, Parconazole Hydrochloride, Paregoric, Pareptide Sulfate, Pargyline Hydrochloride, parnaparin sodium, Paromomycin Sulfate, Paroxetine, paroxetine hydrochloride, parthenolide, Partricin,
Paulomycin, pazelliptine, Pazinaclone, Pazoxide, pazufloxacin, pefloxacin, pegaspargase, Pegorgotein, Pegylated interferon alfa-2a, Pelanserin Hydrochloride, peldesine,
Pelrinone Hydrochloride, Pemedolac, Pemerid Nitrate, Pemetrexed, pemirolast, Pemoline, Penamecillin, Penbutolol Sulfate, Penciclovir, Penfluridol,
Penicillamine, Penicillin G Benzathine, Penicillin G Potassium, Penicillin G Procaine, Penicillin G Sodium, Penicillin V Hydrabamine, Penicillin V Benzathine, Penicillin V Potassium, Pentabamate, Pentaerythritol Tetranitrate, pentafuside, pentamidine,
pentamorphone, Pentamustine, Pentapiperium Methylsulfate, Pentazocine, Pentetic Acid, Pentiapine Maleate, pentigetide, Pentisomicin, Pentizidone Sodium, Pentobarbital,
Pentomone, Pentopril, pentosan, pentostatin, Pentoxifylline, Pentrinitrol, pentrozole, Peplomycin Sulfate, Pepstatin, perflubron, perfofamide, Perfosfamide, pergolide, Perhexiline Maleate, perillyl alcohol, Perindopril, perindoprilat, Perlapin Permethrin, perospirone, Perphenazine, Phenacemide, phenaridine, phenazinomycin, Phenazopyridine Hydrochloride, Phenbutazone Sodium Glycerate, Phencarbamide, Phencyclidine Hydrochloride,
Phendimetrazine Tartrate, Phenelzine Sulfate, Phenformin, Phenmetrazine Hydrochloride, Phenobarbital, Phenoxybenzamine Hydrochloride, Phenprocoumon, phenserine,
phensuccinal, Phensuximide, Phentermine, Phentermine Hydrochloride, phentolamine mesilate, Phentoxifylline, Phenyl Aminosalicylate, phenylacetate, Phenylalanine, phenylalanylketoconazole, Phenylbutazone, Phenylephrine Hydrochloride,
Phenylpropanolamine Hydrochloride, Phenylpropanolamine Polistirex, Phenyramidol Hydrochloride, Phenytoin, Phenytoin sodium, Physostigmine, picenadol, picibanil, Picotrin Diolamine, picroliv, picumeterol, pidotimod, Pifarnine, Pilocarpine, pilsicainide, pimagedine, Pimetine Hydrochloride, pimilprost, Pimobendan, Pimozide, Pinacidil, Pinadoline, Pindolol, pinnenol, pinocebrin, Pinoxepin Hydrochloride, pioglitazone, Pipamperone, Pipazethate, pipecuronium bromide, Piperacetazine, Piperacillin, Piperacillin Sodium, Piperamide Maleate, Piperazinc, Pipobroman, Piposulfan, Pipotiazine Palmitate, Pipoxolan
Hydrochloride, Piprozolin, Piquindone Hydrochloride, Piquizil Hydrochloride, Piracetam, Pirandamine Hydrochloride, pirarubicin, Pirazmonam Sodium, Pirazolac, Pirbenicillin
Sodium, Pirbuterol Acetate, Pirenperone, Pirenzepine Hydrochloride, piretanide, Pirfenidone, Piridicillin Sodium, Piridronate Sodium, Piriprost, piritrexim, Pirlimycin Hydrochloride, pirlindole, pirmagrel, Pirmenol Hydrochloride, Pirnabine, Piroctone, Pirodavir, pirodomast, Pirogliride Tartrate, Pirolate, Pirolazamide, Piroxantrone Hydrochloride, Piroxicam, Piroximone, Pirprofen, Pirquinozol, Pirsidomine, Pivampicillin Hydrochloride, Pivopril, Pizotyline, placetin A, Plicamycin, Plomestane, Pobilukast Edamine, Podofilox, Poisonoak Extract, Poldine Methylsulfate, Poliglusam, Polignate Sodium, Polymyxin B Sulfate, Polythiazide, Ponalrestat, Porfimer Sodium, Porfiromycin, Potassium Chloride, Potassium i;^ PAtQoci Permanganate, Povidone-lodine, Practolol, Pralidoxime Chloride, Pramipexole, Pramiracetam Hydrochloride, Pramoxine Hydrochloride, Pranolium Chloride, Pravadoline Maleate, Pravastatin, Pravastatin sodium, Prazepam, Prazosin, Prazosin
Hydrochloride, Prednazate, Prednicarbate, Prednimustine, Prednisolone, prednisolone quetiapine fumerate, Prednisone, Prednival, Pregabalin, Pregnenolone Succiniate, Prenalterol Hydrochloride, Prenylamine, Pridefine Hydrochloride, Prifelone, Prilocaine Hydrochloride, Prilosec, Primaquine Phosphate, Primidolol, Primidone, Prinivil, Prinomide Tromethamine, Prinoxodan, pritosufloxacin, Prizidilol Hydrochloride, Proadifen Hydrochloride, Probenecid, Probicromil Calcium, Probucol, Procainamide Hydrochloride, Procaine Hydrochloride, Procarbazine Hydrochloride, Procaterol Hydrochloride, Prochlorperazine, Procinonide, Proclonol, Procyclidine Hydrochloride, Prodilidine Hydrochloride, Prodolic Acid, Profadol Hydrochloride, Progabide, Progesterone, Proglumide, Proinsulin (human), Proline, Prolintane Hydrochloride, Promazine Hydrochloride, Promethazine, Promethazine hydrochloride, Propafenone Hydrochloride, propagermanium, Propanidid, Propantheline Bromide,
Proparacaine Hydrochloride, Propatyl Nitrate, propentofylline, Propenzolate Hydrochloride, Propikacin, Propiomazine, Propionic Acid, propionylcarnitine, propiram, propiram, propiverine, Propofol, Proponolol hydrochloride, Propoxycaine Hydrochloride,
Propoxyphene Hydrochloride, Propranolol Hydrochloride, Propulsid, propylbis-acridone, Propylhexedrine, Propyliodone, Propylthiouracil, Proquazone, Prorenoate Potassium, Proroxan Hydrochloride, Proscillaridin, Prostalene, prostratin, Protamine Sulfate, protegrin, Protirelin, Protriptyline Hydrochloride, Proxazole, Proxazole Citrate, Proxicromil,
Proxorphan Tartrate, prulifloxacin, pseudoephedrine, Pseudophedrine hydrochloride, Puromycin, Pyrabrom, Pyrantel Pamoate, Pyrazinamide, Pyrazofurin, pyrazoloacridine, Pyridostigmine Bromide, Pyridoxine hydrochloride, Pyrilamine Maleate, Pyrimethamine, Pyrinoline, Pyrithione Sodium, Pyrithione Zinc, Pyrovalerone Hydrochloride, Pyroxamine Maleate, Pyrrocaine, Pyrroliphene Hydrochloride, Pyrrolnitrin, Pyrvinium Pamoate,
Quadazocine Mesylate, Quazepam, Quazinone, Quazodine, Quazolast, quetiapine, quetiapine fumarate, quiflapon, quinagolide, Quinaldine Blue, quinapril, Quinapril hydrochloride, Quinazosin Hydrochloride, Quinbolone, Quinctolate, Quindecamine Acetate, Quindonium Bromide, Quinelorane Hydrochloride, Quinestrol, Quinfamide, Quingestanol Acetate, Quingestrone, Quinidine Gluconate, Quinielorane Hydrochloride, Quinine Sulfate,
Quinpirole Hydrochloride, Quinterenol Sulfate, Quinuclium Bromide, Quinupristin, Quipazine Maleate, Rabeprazole, Rabeprazole Sodium, Racephenicol, Racepinephrine, Rafoxanide, Ralitoline, raloxifene, raltegravir, raltitrexed, ramatroban, Ramipril,
T? a m™i a« ;« ra rLosetron, ranelic acid, Ranimycin, Ranitidine, Ranitidine hydrochloride, ranolazine, Rauwolfia Serpentina, recainam, Recainam Hydrochloride, Reclazepam, Recombinant factor VIII, regavirumab, Regramostim, Relaxin, Relomycin, Remacemide Hydrochloride, Remifentanil Hydrochloride, Remiprostol, Remoxipride, Repirinast,
Repromicin, Reproterol Hydrochloride, Reserpine, resinferatoxin, Resorcinol, retapamulin, retelliptine demethylated, reticulon, reviparin sodium, revizinone, rhenium etidronate, rhizoxin, RI retinamide, Ribaminol, Ribavirin, Riboprine, ricasetron, Ridogrel, Rifabutin, Rifametane, Rifamexil,. Rifamide, Rifampin, Rifapentine, Rifaximin, rilopirox, Riluzole, rimantadine, Rimcazole Hydrochloride, Rimexolone, Rimiterol Hydrobromide, Rimonabant, rimoprogin, riodipine, Rioprostil, Ripazepam, ripisartan, Risedronate, Risedronate Sodium, risedronic acid, Risocaine, Risotilide Hydrochloride, rispenzepine, Risperdal, Risperidone, Ritanserin, ritipenem, Ritodrine, Ritolukast, ritonavir, rituximab, rivastigmine, rivastigmine tartrate, Rizatriptan, rizatriptan benzoate, Rocastine Hydrochloride, Rocuronium Bromide, Rodocaine, Roflurane, Rogletimide, rohitukine, rokitamycin, Roletamicide, Rolgamidine, Rolicyprine, Rolipram, Rolitetracycline, Rolodine, Romazarit, romurtide, Ronidazole, Ropinirole, Ropitoin Hydrochloride, ropivacaine, Ropizine, roquinimex, Rosaramicin, rosiglitazone, Rosiglitazone maleate, Rosoxacin, Rosuvastatin, Rotavirus vaccine, rotigotine, Rotoxamine, roxaitidine, Roxarsone, roxindole, roxithromycin, rubiginone B l, ruboxyl, rufloxacin, rupatidine, Rutamycin, ruzadolane, Sabeluzole, safingol, safironil, saintopin, salbutamol, Salbutamol sulfate, Salcolex, Salethamide Maleate, Salicyl Alcohol,
Salicylamide, Salicylate Meglumine, Salicylic Acid, Salmeterol, Salnacediin, Salsalate, sameridine, sampatrilat, Sancycline, sanfetrinem, Sanguinarium Chloride, Saperconazole, saprisartan, sapropterin, sapropterin dihydrochloride, saquinavir, Sarafloxacin Hydrochloride, Saralasin Acetate, sarcophytol A, sargramostim, Sarmoxicillin, Sarpicillin, sarpogrelate, saruplase, saterinone, satigrel, satumomab pendetide, Scopafungin, Scopolamine
Hydrobromide, Scrazaipine Hydrochloride, Secalciferol, Secobarbital, Seelzone, segiline, Seglitide Acetate, Selegiline Hydrochloride, Selenium Sulfide, Selenomethionine Se-75, Selfotel, sematilide, semduramicin, semotiadil, semustine, Sepazonium Chloride, Seperidol Hydrochloride, Seprilose, Seproxetine Hydrochloride, Seractide Acetate, Sergolexole Maleate, Serine, Sermetacin, Sermorelin Acetate, sertaconazole, sertindole, sertraline, sertraline hydrochloride, S-ethynyluracil, setiptiline, Setoperone, Sevelamer, sevirumab, sevoflurane, sezolamide, Sibopirdine, Sibutramine Hydrochloride, Silandrone, Sildenafil, sildenafil citrate, silipide, silteplase, Silver Nitrate, simendan, Simtrazene, Simvastatin, Sincalide, Sinefungin, sinitrodil, sinnabidol, sipatrigine, sirolimus, Sisomicin, Sitagliptin, Q^rrin. c.; ^ c;firarij sobuzoxane, Sodium Amylosulfate, Sodium Iodide 1-123, Sodium Nitroprusside, Sodium Oxybate, sodium phenylacetate, Sodium Salicylate, Sodium valproate, Solifenacin, solverol, Solypertine Tartrate, Somalapor, Somantadine Hydrochloride, somatomedin B, somatomedin C, Somatostatin, somatrem, somatropin, Somenopor,
Somidobove, Sorbinil, Sorivudine, sotalol, Soterenol Hydrochloride, Sparfioxacin, Sparfosate Sodium, sparfosic acid, Sparsomy, Sparteine Sulfate, Spectinomycin Hydrochloride, spicamycin D, Spiperone, Spiradoline Mesylate, Spiramycin, Spirapril Hydrochloride, Spiraprilat, Spirogermanium Hydrochloride, Spiromustine, Spironolactone, Spiroplatin, Spiroxasone, splenopentin, spongistatin, Sprodiamide, squalamine, Stallimycin
Hydrochloride, Stannous Pyrophosphate, Stannous Sulfur Colloid, Stanozolol, Statolon, staurosporine, stavudine, Steffimycin, Stenbolone Acetate, stepronin, Stilbazium Iodide, Stilonium Iodide, stipiamide, Stiripentol, stobadine, Streptomycin Sulfate, Streptonicozid, Streptonigrin, Streptozocin, Strontium Chloride Sr-89, succibun, Succimer, Succinylcholine Chloride, Sucralfate, Sucrosofate Potassium, Sudoxicam, Sufentanil, Sufotidine, Sulazepam, Sulbactam Pivoxil, Sulconazole Nitrate, Sulfabenz, Sulfabenzamide, Sulfacetamide,
Sulfacytine, Sulfadiazine, Sulfadoxine, Sulfalene, Sulfamerazine, Sulfameter,
Sulfamethazine, Sulfamethizole, Sulfamethoxazole, Sulfamonomethoxine, Sulfamoxole, Sulfanilate Zinc, Sulfanitran, sulfasalazine, Sulfasomizole, Sulfazamet, Sulfinalol
Hydrochloride, sulfinosine, Sulfinpyrazone, Sulfisoxazole, Sulfomethoxazole, Sulfomyxin, Sulfonterol Hydrochloride, sulfoxamine, Sulinldac, Sulmarin, Sulnidazole, Suloctidil, Sulofenur, sulopenem, Suloxifen Oxalate, Sulpiride, Sulprostone, sultamicillin, Sulthiame, sultopride, sulukast, Sumarotene, sumatriptan, Sumatriptan succinate, Suncillin Sodium, Suproclone, Suprofen, suradista, suramin, Surfomer, Suricainide Maleate, Suritozole, Suronacrine Maleate, Suxemerid Sulfate, swainsonine, symakalim, Symclosene, Symetine Hydrochloride, Taciamine Hydrochloride, Tacrine Hydrochloride, Tacrolimus, Tadalafil, Talampicillin Hydrochloride, Taleranol, Talisomycin, tallimustine, Talmetacin, Talniflumate, Talopram Hydrochloride, Talosalate, Tametraline Hydrochloride, Tamoxifen, tamoxifen citrate, Tampramine Fumarate, Tamsulosin, Tamsulosin Hydrochloride, Tandamine
Hydrochloride, tandospirone, tapgen, taprostene, Tasosartan, tauromustine, Taxane, Taxoid, Tazadolene Succinate, tazanolast, tazarotene, Tazifylline Hydrochloride, Tazobactam, Tazofelone, Tazolol Hydrochloride, Tebufelone, Tebuquine, Teclozan, Tecogalan Sodium, Teecleukin, Teflurane, Tegafur, Tegaserod, Tegretol, Teicoplanin, telenzepine,
tellurapyrylium, telmesteine, telmisartan, Teloxantrone Hydrochloride, Teludipine
Hydrochloride, Temafloxacin Hydrochloride, Tematropium Methyl sulfate, Temazepam,
^mocapril, Temocillin, temoporfin, temozolomide, temsirolimus, Tenidap, Teniposide, Tenofovir, tenosal, tenoxicam, tepirindole, Tepoxalin, Teprotide, terazosin, Terazosin Hydrochloride, Terbinafine, Terbutaline Sulfate, Terconazole, terfenadine, terfiavoxate, terguride, Teriparatide, Teriparatide Acetate, terlakiren, terlipressin, terodiline, Teroxalene Hydrochloride, Teroxirone, tertatolol, Tesicam, Tesimide, Testolactone,
Testosterone, Tetracaine, tetrachlorodecaoxide, Tetracycline, Tetracycline hydrochloride, Tetrahydrozoline Hydrochloride, Tetramisole Hydrochloride, Tetrazolast Meglumine, tetrazomine, Tetrofosmin, Tetroquinone, Tetroxoprim, Tetrydamine, thaliblastine,
Thalidomide, Theofibrate, Theophylline, Thiabendazole, Thiamiprine, Thiamphenicol, Thiamylal, Thiazesim Hydrochloride, Thiazinamium Chloride, Thiethylperazine, Thiithixene, Thimerfonate Sodium, Thimerosal, thiocoraline, thiofedrine, Thioguanine, thiomarinol, Thiopental Sodium, thioperamide, Thioridazine, Thiotepa, Thiphenamil Hydrochloride, Thiphencillin Potassium, Thiram, Thozalinone, Threonine, Thrombin, thrombopoietin, thymalfasin, thymopentin, thymotrinan, Thyromedan Hydrochloride, Thyroxine, Tiacrilast, Tiacrilast Sodium, tiagabine, Tiamenidine, tianeptine, tiapafant, Tiapamil Hydrochloride, Tiaramide Hydrochloride, Tiazofurin, Tibenelast Sodium, Tibolone, Tibric Acid, Ticabesone Propionate, Ticarbodine, Ticarcillin Cresyl Sodium, Ticlatone, ticlopidine, Ticrynafen, tienoxolol, Tifurac Sodium, Tigemonam Dicholine, Tigestol, Tiletamine Hydrochloride, Tilidine Hydrochloride, tilisolol, tilnoprofen arbamel, Tilorone Hydrochloride, Tiludronate Disodium, tiludronic acid, Timefurone, Timobesone Acetate, Timolol, Timolol meleate, Tinabinol, Tinidazole, Tinzaparin Sodium, Tioconazole, Tiodazosin, Tiodonium Chloride, Tioperidone Hydrochloride, Tiopinac, Tiospirone Hydrochloride, Tiotidine, Tiotropium, tiotropium bromide, Tioxidazole, Tipentosin Hydrochloride, tipranavir, Tipredane, Tiprenolol Hydrochloride, Tiprinast Meglumine, Tipropidil Hydrochloride, Tiqueside, Tiquinamide Hydrochloride, tirandalydigin, Tirapazamine, tirilazad, tirofiban, tiropramide, titanocene dichloride, Tixanox, Tixocortol Pivalate, Tizanidine Hydrochloride, Tnmethobenzamide Hydrochloride, Tobramycin, Tocainide, Tocamphyl, Tofenacin Hydrochloride, Tolamolol, Tolazamide, Tolazoline Hydrochloride, Tolbutamide, Tolcapone, Tolciclate, Tolfamide, Tolgabide, Tolimidone, Tolindate, Tolmetin, Tolnaftate, Tolpovidone, Tolpyrramide, Tolrestat, Tolterodine, tolterodine tartrate, Tomelukast, Tomoxetine Hydrochloride,
Tonazocine Mesylate, Topiramate, topotecan, Topotecan Hydrochloride, topsentin,
Topterone, Toquizine, torasemide, toremifene, Torsemide, Tosifen, Tosufloxacin, totipotent stem cell factor (TSCF), Tracazolate, trafermin, Tralonide, Tramadol, Tramadol
Hydrochloride, Tramazoline Hydrochloride, trandolapril, Tranexamic Acid, Tranilast,
Tranc^ in tra stuzumab, traxanox, Trazodone Hydrochloride, Trebenzomine Hydrochloride, Trefentanil Hydrochloride, Treloxinate, Trepipam Maleate, Trestolone Acetate, tretinoin, Triacetin, triacetyluridine, Triafungin, Triamcinolone, Triampyzine Sulfate, Triamterene, Triazolam, Tribenoside, tricaprilin, Tricetamide, Trichlormethiazide, trichohyalin, triciribine, Tricitrates, Triclofenol Piperazine, Triclofos Sodium, trientine, Trifenagrel, triflavin, Triflocin, Triflubazam, Triflumidate, Trifluoperazine Hydrochloride, Trifluperidol, Triflupromazine, Triflupromazine Hydrochloride, Trifluridine,
Trihexyphenidyl Hydrochloride, Trilostane, Trimazosin Hydrochloride, trimegestone, Trimeprazine Tartrate, Trimethadione, Trimethaphan Camsylate, Trimethoprim, Trimetozine, Trimetrexate, Trimipramine, Trimoprostil, Trimoxamine Hydrochloride, Triolein, Trioxifene Mesylate, Tripamide, Tripelennamine Hydrochloride, Triprolidine Hydrochloride,
Triptorelin, Trisulfapyrimidines, Troclosene Potassium, troglitazone, Trolamine,
Troleandomycin, trombodipine, trometamol, Tropanserin Hydrochloride, Tropicamide, tropine, tropisetron, trospectomycin, trovafloxacin, trovirdine, Tryptophan, Tuberculin, Tubocurarine Chloride, Tubulozole Hydrochloride, tucarcsol, tulobuterol, turosteride, Tybamate, tylogenin, Tyropanoate Sodium, Tyrosine, Tyrothricin, tyrphostins, ubenimex,
Uldazepam, Undecylenic Acid, Uracil Mustard, urapidil, Urea, Uredepa, uridine triphosphate, Urofollitropin, Urokinase, Ursodiol, valaciclovir, Valacyclovir hydrochloride, Valine, Valnoctamide, Valproate semisodium, Valproic Acid, valsartan, vamicamide, vanadeine, Vancomycin, vaninolol, Vapiprost Hydrochloride, Vapreotide, Vardenafil, Varenicline, variolin B, Vasopressin, Vecuronium Bromide, velaresol, Velnacrine Maleate, venlafaxine, Venlafaxine hydrochloride, Veradoline Hydrochloride, veramine, Verapamil Hydrochloride, verdins, Verilopam Hydrochloride, Verlukast, Verofylline, veroxan, verteporfin,
Vesnarinone, vexibinol, Vidarabine, vigabatrin, vildagliptin, Viloxazine Hydrochloride, Vinblastine Sulfate, vinburnine citrate, Vincofos, vinconate, Vincristine Sulfate, Vindesine, Vindesine Sulfate, Vinepidine Sulfate, Vinglycinate Sulfate, Vinleurosine Sulfate, vinorelbine, vinpocetine, vintoperol, vinxaltine, Vinzolidine Sulfate, Viprostol,
Virginiamycin, Viridofulvin, Viroxime, vitaxin, Voglibose, Volazocine, voriconazole, vorozole, voxergolide, Wafarin , Xamoterol, Xanomeline, Xanoxate Sodium, Xanthinol Niacinate, xemilofiban, Xenalipin, Xenbucin, Xilobam, ximoprofen, Xipamide, Xorphanol Mesylate, Xylamidine Tosylate, Xylazine Hydrochloride, Xylometazoline Hydrochloride, xylose, yangambin, zabicipril, zacopride, zafirlukast, Zalcitabine, Zaleplon, zalospirone, Zaltidine Hydrochloride, zaltoprofen, zanamivir, zankiren, zanoterone, Zantac, Zarirlukast, zatebradine, zatosetron, Zatosetron Maleate, zenarestat, Zenazocine Mesylate, Zeniplatin, 7pran l 7;rl^™^tacin, Zidovudine, zifrosilone, Zilantel, zilascorb, zileuton, Zimeldine Hydrochloride, Zinc Undecylenate, Zindotrine, Zinoconazole Hydrochloride, Zinostatin, Zinterol Hydrochloride, Zinviroxime, ziprasidone, Zobolt, Zofenopril Calcium, Zofenoprilat, Zolamine Hydrochloride, Zolazepam Hydrochloride, Zoledronate, Zolertine Hydrochloride, zolmitriptan, Zolpidem, Zomepirac Sodium, Zometapine, Zoniclezole Hydrochloride, Zonisamide, zopiclone, Zopolrestat, Zorbamyciin, Zorubicin Hydrochloride, zotepine, Zucapsaicin, and pharmaceutically acceptable salts thereof.

Claims

Claims:
1. A device for administering a therapeutic agent, the device comprising:
an implantable delivery device comprising a reservoir;
a channeled member in fluid communication with the reservoir; and
a solid matter therapeutic agent disposed within the reservoir and in fluid
communication with the channeled member.
2. The device of claim 1 wherein the channeled member comprises nanochannels.
3. The device of claim 1 wherein the channeled member comprises microchannels.
4. The device of claim 1 wherein the solid matter therapeutic agent comprises a gel.
5. The device of claim 1 wherein the solid matter therapeutic agent comprises a paste.
6. The device of claim 1 wherein the solid matter therapeutic agent comprises a dry solid.
7. The device of claim 6 wherein the dry solid comprises crystals, granules, or particles.
8. The device of claim 1 wherein the solid matter therapeutic agent comprises a powder.
9. The therapeutic agent delivery device of claim 6 wherein the dry solid is formed as a tablet.
10. The therapeutic agent delivery device of claim 1 wherein the solid matter comprises a polymer matrix in which the therapeutic agent is mixed.
11. The therapeutic agent delivery device of claim 1 wherein the therapeutic agent delivery device comprises an injection port configured to receive an injection of the solid matter therapeutic agent.
12. A method of administering a therapeutic agent, the method comprising:
inserting an implantable delivery device into an area of a human anatomy, wherein the implantable delivery device comprises:
a reservoir;
a channeled member in fluid communication with the reservoir; and a solid matter therapeutic agent disposed within the reservoir; and releasing a portion of the therapeutic agent from the implantable delivery device into the area of the human anatomy.
13. The method of claim 12 wherein the implantable delivery device is configured to release the therapeutic agent at a substantially constant release rate for a dosage period of at least one week.
14. The method of claim 12 wherein the implantable delivery device is configured to release the therapeutic agent at a substantially constant release rate for a dosage period of at least one month.
15. The method of claim 12 wherein the implantable delivery device is configured to release the therapeutic agent at a substantially constant release rate for a dosage period of at least six months.
16. The method of claim 12 wherein the implantable delivery device is configured to release the therapeutic agent at a substantially constant release rate for a dosage period of at least one year.
17. The method of claim 12 wherein the reservoir comprises a solvent configured to dissolve the solid matter therapeutic agent.
18. The method of claim 17 wherein the solvent is water.
19. The method of claim 17 wherein the solvent is water with dissolved components
including salts and minerals to approximate the composition of physiologic serum.
20. The method of claim 12 wherein the reservoir comprises a saturated solution of the therapeutic agent.
21. The method of claim 12 wherein the reservoir comprises a supersaturated solution of the therapeutic agent.
22. The method of claim 12 wherein the implantable delivery device comprises a filter.
23. The method of claim 22 wherein the filter is disposed between the solid matter
therapeutic agent and the channeled member.
24. The method of claim 22 wherein the filter is disposed between the solid matter
therapeutic agent and a therapeutic component.
25. The method of claim 22 wherein the filter comprises nanochannels.
26. The method of claim 12 wherein the channeled member comprises microchannels.
27. The method of cliam 12 wherein the channeled member comprises nanochannels.
PCT/US2012/061536 2011-10-24 2012-10-24 Device and method for sustained release of therapeutic agent WO2013063004A1 (en)

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CA2853347A CA2853347A1 (en) 2011-10-24 2012-10-24 Device and method for sustained release of therapeutic agent
EP12843467.7A EP2770984A4 (en) 2011-10-24 2012-10-24 Device and method for sustained release of therapeutic agent

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CA2853347A1 (en) 2013-05-02
EP2770984A4 (en) 2015-07-01

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